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P.1 
^Original Articles 

ead and Hyperactivity Revisited 

An Investigation of Nondisadvantaged Children 

P.2 

examine whether hypoxic 

•.SO'J 

. iispring. 

i weU- " 

iution 

seen 

• The purposes^Tffls"stuly^?efe^ 

tractive children had elevated lead levels, to assess whether 

tad levels were associated with poor psychometric performaKein hyperactive children, and to replicate previous reports 

tf hyperactive children with perinatal Insult having lower lead 

M s than those with normal perinatal history. Hyperactive, 

taming-disabled children and normal siblings were studied. 

tte hyperactive children had higher chelated urine lead levels 

ten their own siblings. Other contrasts were not significant. 

Cognitive performance and lead levels were weakly associated 

' sthe hyperactive sample. Contrary to previous reports, lead 

•• pds and perinatal complications were not negatively corre-

\ Mtd. These results support the notion that lead levels are 

* acakly associated with hyperactive disorders. 

tfncb Gen Psychiatry 1983;40:827-833) 

^Ithough the sequelae of large doses of lead are well 

!/!. known,1,2 the effects of long-term, low levels of absorpXm remain unclear. Most studies have reported that Chilian with raised lead levels, not formerly believed to be in 

& toxic range, show slight but often significant decree t s in cognition and behavior. For example, raised lead 

iirels have been found to be associated with lower intellipoorer academic skills,6

 and increased motor activ-

.•iii ana 

. or loss. 

FDavid and co-workers9 reported that black, inner-city, 

:.;

t

'°y^c_ Sjperactive children had higher lead levels than nonhyper-

) Taj! ', save children from the same area. Lead levels were 

ne ;; assured in urine after provocation with penicillamine, and 

•jmbness. jMood. Defining toxic urine lead levels as greater than 

'^J

a

xrri;' USmg/L, David et al found that 62% ofthe hyperactive 

•Tbdomirai Sildren, but only 29% ofthe nonhyperactive children, had 

icbsec id levels in the toxic range. Furthermore, among the 

jperactive youngsters, lead levels were negatively associttd with perinatal risk factors. David et al divided the 

1 pperactive children into three groups, one without a his-

<.;:onsnip : ay of perinatal complications (N = 50), another with a hisnergic- gy 0f serious perinatal complications viewed as "highly 

~ and Ne^ J^ble

 cau ses " of hyperactivity (N = 5), and a third group 

^bocytopa -& complications less severe than those of the "probable" 

ange in j jbap but judged to be "possible" causes of hyperactivity 

- ce. uri- ', $=<)). The children with "probable" causes were found to 

BB significantly lower lead levels than the other two 

roips. Furthermore, the proportion of children in the toxic 

.•tract. •'• age differed among the. three etiologic subgroups. Of 

opriate iase without any cause for hyperactivity, 31 (62%) had 

. !f

 G

.

a

a

s

-. sic lead levels, and of those with probable cause, seven! 

• 3%) had toxic lead levels; in contrast, one (20%) of those | 

,.., aha highly probable cause had a toxic lead level. 

iressatt 

• any 

3.Pruso»a»;ltepted for publication Nov 5, 19S2. 

:ou!patien3-^JVijin the New York State Psychiatric Institute, Columbia University 

eof Physicians and Surgeons, New York (Dr Gittelman); and the John 

ree Foundation and the Department of Epidemiology and Public 

Utli, Yale School of Medicine, New Haven, Conn (Dr Eskenazi). 

'JtfciM requests to New York State Psychiatric Institute, Columbia 

•ersity College bf Physicians and Surgeons, 722 W 168th St, New York, 

110032 (Dr Gittelman). 

x 

J. di Gen Psychiatry—Vol 40, Aug 1983 

Rachel Gittelman, PhD, Brenda Eskenazi. PhD 

David and colleagues concluded that low-level lead intoxication may play an etiologic role in some cases of hyperactivity, notably in children without perinatal complications. 

Their sample sizes, however, were too small to allow for firm 

conclusions. In a subsequent larger study, David and coworkers'" did not replicate the significant difference in lead 

levels between hyperactive children with and those without 

perinatal complications, though a trend was found. 

Some methodological problems complicate the interpretation of those results. Perinatal history was taken from 

chart review, and information was derived from routine 

clinical interviews without standardized procedures. In 

addition, the socioeconomic status ofthe respective groups 

was not indicated. The association of lead levels with 

hyperactivity and its putative etiologic subtypes could be 

confounded by socioeconomic status." Even if the various 

groups were equivalent in social class, the results may be 

specific to socially deprived groups. 

The purpose of the present study was to examine lead 

levels in nondisadvantaged hyperactive children with wellconfirmed socioeconomic status (SES). The goals were to 

assess (1) whether lead levels were higher in hyperactive 

children than normal children; (2) whether elevated lead 

levels in hyperactive youngsters, if found, were specific to 

this diagnostic group; (3) whether the negative relationship 

between perinatal complications and lead levels in hyperactive children could be replicated; (4) whether lead level was 

associated with severity of hyperactivity; and (5) whether 

the negative association between cognitive performance 

and lead exposure reported in normal children3'

58

 also 

occurred in hyperactive children. 

SUBJECTS AND METHODS 

Samples 

Three groups were included in this investigation: (1) nondisadvantaged hyperactive children; (2) normal children; and (3) nondisadvantaged children with a developmental disorder other than 

hyperactivity (learning-disabled children). Except for the normal 

children, all children had participated in clinical trials between 

1971 and 1975. Details ofthe selection procedures are summarized 

only briefly since they appear elsewhere.12'

1

'

1

 All children lived in 

suburban areas of New York City. 

Hyperactive Children.—The hyperactive children were part of 

two separate studies in which slightly different clinical criteria 

were applied. Both studies required the children to demonstrate 

cross-situational hyperactivity. 

At the time of the first study,12 no objective scale criteria had 

been established to quantify hyperactivity in the classroom; 

therefore, arbitrary standards for hyperactivity were applied. 

Children had to receive a minimum score of 2 (range, 0 to 3) on 

several items ofthe Teacher Rating Scale15 that reflect inattention 

and impulsivity. In addition, children were accepted only if rated 

hyperactive by parents on the Home Hyperactivity Scale,16 or 

judged hyperactive in the clinic. 

In the second study,13 children referred by schools for hyperactivity had to receive scores of at least 1.8 (of a possible maximum of 

3.0) on the hyperactivity factor of the Teacher Rating Scale. 

Parents had to confirm the presence of clear behavior problems at 

Lead and Hyperactivity—Gittelman & Eskenazi 
P.3 

\~ 

Table 1.—Weightings and Frequencies of Perinatal 

Complications* 

Complications 

Pregnancy 

Mild 

Maternal age >30 yr for firstborn, >40 yr for 

others 

>3 miscarriages before this birth 

>3 miscarriages after this birth 

Medical intervention to conceive this child 

Severe nausea and vomiting extending into third 

trimester 

Mild staining after first trimester 

Mild bleeding; threatened abortion during 

first trimester 

Mild bleeding; threatened abortion after first 

trimester 

Mild toxemia 

Mildly elevated BP 

Weight gain of >20.5 kg 

Controlled diabetes 

Otner mild healtn problems 

Abdominal x-ray film 

Infectious disease during first trimester 

Infectious disease after first trimester 

Other illness after first trimester 

Surgery with general anesthesia 

Unusual medication 

Mild physical trauma 

Mild emotional stress 

Moderate 

Moderate bleeding; threatened abortion after first 

trimester 

Moderate toxemia 

Moderately high BP 

Other moderate heaith problems 

Severe emotional stress 

No. of 

Subjects 

8 

11 

14 

15 

8 

2 

3 

3 

8 

4 

8 

1 

15 

6 

3 

6 

1 

1 

2 

2 

1 

1 

4 

3 

1 

2 

Table 1.—Weightings and Frequencies of Perinatal 

Complications* (cont) 

Complications 

No. . 

Subjc 

Labor and delivery 

Mild 

Extended labor (stage.1 (or >24 hr, or stage 2 for 

>2 hr) 

Precipitate labor 

Premature membrane rupture (24-48 hr) 

Cord around neck (not prolapsed) 

Routine cesarean delivery 

Abnormal position 

Moderate 

Cesarean delivery medically indicated 

Neonatal condition 

Mild 

Delayed breathing for 1-3 min 

Weak or abnormal cry 

Mild/intermittent cyanosis 

Oxygen given for 2 min 

Apgar score of 7 or 8 

Mild congenital defect 

Mild illness for 1 wk 

Rh or other blood incompatibility 

Birth weight of 2.0-2.4 kg 

Gestation of >43 wk 

Moderate 

Apgar score of 5 or 6 

i 

3 

2 

4 

6 

e 

£ 

o 

"> 

o 

Severe 

Apgar score of 1 or 4 

•Complications not found included the following: attempt to abort th 

convulsions during pregnancy; uncontrolled diabetes; severe t 

moderate or severe staining after third trimester; severe other 

problems during pregnancy; medical indication to induce labor; <. 

delayed; midforceps or high forceps delivery; manual or forceps -. 

premature separation of membrane; fetal distress; breathing de;. 

more than three minutes; cry delayed for more than 15 minutes; pc 

cyanosis; continuous oxygen given; abnormal condition of head fmarks, cephalhematoma); and prolapsed cord. 

home, and a psychiatrist had to diagnose the child as having a 

hyperkinetic reaction of childhood.IT 

Both studies required children to be between 6 and 12 years old, 

to come from homes where English was spoken, and to be free of a 

psychotic or neurological disorder (the presence of nonspecific 

neurological abnormalities or signs did not preclude admission). 

Children also had to obtain an IQ of at least 80 on the Wechsler 

Intelligence Scale for Children (WISC), with either a performance 

or verbal IQ of at least 85. 

Nonhyperactive Learning-Disabled Children.—To obtain a 

group with a developmental disorder other than hyperactivity, we 

recruited children with reading disabilities. This group seemed 

most appropriate since it represented a relatively homogeneous 

dysfunction that is often assumed to be a phenotypic expression of 

minimal brain dysfunction, as is hyperactivity.18 

To be included, children had to (1) be referred by school because 

of academic difficulties exclusively; (2) have no complaint of 

behavior problems; (3) receive scores below 1.5 on the hyperactivity factor of the Teacher Rating Scale; (4) be judged by a child 

psychiatrist as having no psychiatric disorder other than the 

learning disorder; (5) have no known neurological disorder; (6) have 

an overall WISC IQ of SO, with a performance or verbal IQ of 85; 

(7) have a reading level at least one or two years below their ageappropriate grade (depending on IQ) on the Wide Range Achievement Test (WRAT) and Gray Oral Reading (GOR) Test; and 

(8) come from a home where English was spoken. 

Normal Children.—To control for socioeconomic status, parental practices, and other environmental factors that might influence 

exposure to lead, the normal siblings of the two patient groups 

were selected as controls. They were between 6 and 12 yt-i 

and were reported by parents to have had no behavior prob; 

school and no history of academic difficulties. 

If more than one normal sibling w

r

ere within the appropri 

range, all were included. No neuropsychological testii 

conducted on the siblings. It seems reasonable to assume tl 

siblings were of average intelligence, since they had no hi.-

academic difficulties. Moreover, their hyperactive siblings v 

normal IQ, and we have found that normal siblings of hypo 

children from this population have higher IQs than their h; 

tive siblings.19 

Lead Levels 

The procedure for evaluating lead levels was identical :• 

reported by David et al.9 Each child received at bedtime 25-: 

the chelating agent penicillamine (Cuprimine). The first m< 

urine specimen was collected in lead-free plastic bottles, 

mens were frozen until delivery to the City of New York lab» 

where they were analyzed for lead content. (This laborati. 

selected because it.had performed the analyses for the sn. 

David et al.910) Analyses were performed without knowledge 

children's group membership. Since a total night's uri:-. 

needed, children with enuresis were excluded. Those all 

penicillin were also excluded. (Since prospective studies ci 

ing children's blood lead levels over time to single mea.s: 

chelated lead levels have not been performed, we cannot be i 

that the latter accurately reflects body lead burden due u. 

term exposure. David et al reported that chelated lead lc 

urine were correlated with blood levels. We found that cl. 

828 Arch Gen Psychiatry—Vol 40, Aug 1983 Lead and Hyperactivity—Gittelman & Ei 
P.4 

.c-250mg«v?yPeractives v normal siblings: r(134) = 1.40. P=.16; hyperactives v 

"•< moraine Bnirig-disabled children: f(132) = 0.45, P=.65; learning-disabled children 

les. Spec 

Tial siblings: f(62) = 1.36, P=.18. 

-. laborato? p. 

ratory « id levels of hyperactives and their siblings were highly associ-

..e studies) id, suggesting that the measure is reliable; nevertheless, its 

ledge of ti fidity for measuring lead burden remains unestablished.) 

urine w fcr 

.' allergic! t\ Other Clinical Measures 

.'lies compl ifainatal Complications.—Pregnancy, labor and delivery, and 

measures,' natal history of the hyperactive children were obtained from 

• it be certj jjpjtai records, and also from mothers by means of a standardized 

due to loflfestionnaire given by a social worker or psychologist. Since 

. ud leve^Jkiui interviewing was possible only when the research staff was 

.hat chelaSfciable, not all mothers were questioned. No systematic samGen Psychiatry—Vol 40, Aug 1983 

plinir bias, however, influenced which mothers were interviewed. 

Three approaches were used to assess perinatal difficulties: 

(1) Children were dichotomized between those without any report 

of perinatal insult and those w^ith at least one abnormal finding. (2) 

Perinatal complications were weighted for severity from 1 to 4, 

with 1 indicating nonsignificant or no complication; 2, mild; 3, 

moderate; and 4, severe. These weights were adopted from other 

studies.1'" The items with their respective weights are presented in 

Table 1. Mean score for each perinatal category was obtained by 

summing all severity scores and dividing the sum by the number of 

items rated. (3) Based on a composite of prenatal, labor and 

delivery, and neonatal complications, the perinatal histories were 

classified for each child as clearly abnormal, borderline abnormal, 

or unremarkable. These categories are analagous to David and 

colleagues' classifications of probable cause, possible cause, and no 

history. 

Severity of Illness.—The hyperactivity factor of the Teacher 

Rating Scale1'' and a global rating of illness were used as an 

estimate of severity of behavioral disturbance. Severity of illness 

was rated by a child psychiatrist after a diagnostic evaluation. It 

was scored from 1 to 7, higher scores indicating greater overall 

psychiatric disturbance. 

Neuropsychological Performance.—Hyperactive children 

were evaluated on a battery of neuropsychological tests, including 

the WISC; the WRAT, a test of word recognition, spelling, and 

arithmetic; the GOR test, a test of paragraph reading and comprehension;and the Beery-Buktenica test of Visual Motor Integration 

(VMI), a test of design copying. 

In addition, the hyperactive children who participated in the 

first study were tested on the Visual Sequential Memory Test ofthe 

Illinois Test of Psycholinguistic Ability and a visual paired-associate test, a rote-learning task where the child was required to name 

the object paired with each of ten symbols (the score was the 

number of trials needed to learn the ten object-symbol pairs). 

Data Analyses.—The data were analyzed to assess whether the 

hyperactive children, normal siblings, and nonhyperactive learning disabled children differed significantly in (1) lead distribution; 

(2) mean lead level; ancl (3) the proportion of children in the range 

defined by David et al as toxic, that is, greater than 0.08 mg/L. 

We examined the possible confounding effects of SES, race, age, 

and gender on group differences in lead level. These confounders 

were controlled in the statistical analysis when appropriate. 

To provide further control over SES, race, parental IQ, and any 

other possible environmental factors, hyperactive children were 

paired with one of their own siblings. The lead levels of the pairs 

were contrasted. 

Analyses within the hyperactive group were performed tq assess • 

the relationship between lead exposure and (1) severity of behavior 

disturbance, (2) perinatal factors, and (3) neuropsychological test 

performance. All probability values reported are two-tailed. 

RESULTS 

Sample 

Parents of 173 hyperactive or learning-disabled children were 

approached. Eight refused to have their child participate and three 

children refused to cooperate. Of the remaining 162 children, 28 

were excluded (four were bed wetters and 24 were allergic to penicillin). The final groups consisted of 103 hyperactives, 31 nonhyperactive learning-disabled children, and 33 normal sibling controls. 

Table 2 presents the sample characteristics. The children were 

predominantly male, white, and about 10 years old. The proportion 

of boys was significantly larger in the hyperactive group than in the 

other two groups (P<.001). This sex distribution reflects the 

typical preponderance of boys among children referred for hyperactivity, as compared with children referred for learning problems. 

Group Differences in Lead Levels 

The group distributions of lead levels appear in Fig 1. The overall 

proportions in lead values for the three groups did not differ 

significantly (x"[4] = 6.33, not significant). 

As shown in Table 3, no significant differences in mean lead 

levels were found between hyperactive children and the sibling 

controls (£[134]= 1.40, not significant [NS]), between hyperactive 

children and learning-disabled children (([132] = 0.45, NS), or between learning-disabled children and sibling controls (<[62] = 1.35, 

NS). 

Lead and Hyperactivity—Gittelman & Eskenazi 829 
P.5 

3 

3 

Table 4.—Sample Characteristics and Lead Levels of 

20 Hyperactive-Sibling Pairs 

Age, yr (mean ± 

% male* 

% white 

Lead, mg/L 

Mean sSD f 

Range 

SD) 

Distribution^ No. of 

subjects 

0.00-0.08 

0.09-0.16 

0.17-0.24 

>0.24 

Hyperactives 

10.0 ±2.5 

85 

80 

0.12*0.09 

0.03-0.35 

9 

8 

1 

2 

Paired Normal Siblings 

10.4*1.9 

55 

80 

0.08 ±0.05 

0.02-0.22 

13 

6 

1 

0 

V(1) = 4.3, P=.04. 

tf(19) = 2.52, P=.02. 

tFor levels >0.08 v sO.08 mg/L, *2(1) = 1.62, P = .20. 

0.35 

mg/L els, Lev 

•o 

ta ves' >ract Hype 

0.30 

0.25 

0.20 

0.15 

0.10 

0.05 

0.00 

0.05 0.10 0.15 0.20 0.25 0.30 0.35 

Siblings' Lead Levels, mg/L 

Fig 2.—Paired lead levels of hyperactive children and their normal 

siblings (/'=.69, P<.01) (N = 20 siblings). 

Table 5.—Lead Levels in Hyperactive 

Hyperactives 

Levels >0.08 mg/L 

Levels =s0.08 mg/L 

Hyperactives > 

Siblings 

9 

2 

-Sibling Pairs* 

Hyperactives < 

Siblings 

2 

7 

•Fisher's exact test, P = .02 (two tailed). 

Fifty-eight percent of the hyperactives and 39% of the normal 

children had lead levels greater than 0.08 mg/L (x2[l] = 3.57, 

P-.06). Of the learning-disabled group, 55% had levels above 

0.08 mg/L (the two patient groups obviously did not differ; 

learning-disabled children v normals: x

2

[l]= 1-53, NS). 

Possible Confounders 

The relationship between lead levels and SES, race, age, and 

gender was examined. 

SES and Race.—Socioeconomic status as measured by the 

Hollingshead Scale21 did not correlate significantly with lead levels 

in any of the three groups (hyperactives: Pearson's r[100] = .15, 

P=.13; learning-disabled children: r[29] = .07, NS; sibi-"-

r[30]=-.05, NS). 

The small percentage of black children did not have significa! 

higher lead levels than the white children in any of the gro 

(t = - 1.27 to 0.97). Since neither SES nor race was significa: 

related to lead levels, we did not control for these variables in 

analysis for group contrasts in lead levels. 

Age.—In the hyperactive group, age was significantly ne 

tively correlated with lead level, older children having lower le-. 

(r[101] = - .25, P = .01). A nonsignificant negative trend was fo 

between age and lead levels in the learning-disabled gr-

(r[29] = .32, P<.10). No relationship between age and lead Itwas found in the normal siblings (r[31]= -.17, NS). 

Because of the significant relationship between age and ! 

levels in the hyperactive group, the group contrasts in mean !• 

levels were reanalyzed in an analysis of covariance controlling 

age. Lead levels for the three groups remained indistinguish. 

(hyperactives v siblings: F[l,133] = 0.47, NS; hyperactivelearning-disabled children: Ffl, 131] = 2.32, NS; learning-disat 

children v siblings: F[l,61] = 0.46, NS). 

Gender.—If males have an inherently greater propensity 

accumulate lead, the disproportionate number of boys in 

hyperactive group might have influenced group differences. Th>. 

fore, we compared the lead levels of the boys and girls in <?: 

group. The mean lead levels of the 17 male and the 16 fen 

siblings were almost identical (0.09±0.05 v 0.08±0.05 mp 

respectively; f.[31] = 0.93, NS). The lead levels of the boys . 

girls in the hyperactive group and in the learning-disabled gr 

were also not significantly different (hyperactives: 0.11*0.(r 

0.08±0.03 mg/L, respectively; <[101] = 1.30; learning-disab 

children: 0.10± 0.06 v 0.13 ±0.12 mg/L, respectively; £[29] = - ! 

Pairwise Comparisons of Lead Levels In 

Hyperactive Children and Their Siblings 

We were able to pair 20 of the hyperactive children with on 

their siblings. If a hyperactive child had more than one sib! 

whose lead level had been determined, we selected for compari 

the sibling closest in age. Demographic characteristics of 

hyperactive-sibling pairs appear in Table 4. Again, there v, 

significantly more boys in the hyperactive sample (x2(17) = -

F = .04). 

The distribution and mean lead levels for the pairs are showTable 4. The hyperactive children had significantly higher ir. 

lead levels than their siblings (paired ([19] = 2.52, P = .02). 7 

proportions of children with toxic lead levels did not differ sigr 

cantly between the two groups (x2[2] = 2.7, NS); 55% of" 

hyperactives and only 35% of their siblings had lead levels in 

"toxic" range. 

Figure 2 plots the lead levels of each hyperactive child aga. 

that of his or her sibling. The lead values' of the hype, 

tive children were significantly related to those of their sibli: 

(r[18] = .69, P<.001). A cubic function provided a notably, 

not significantly, better fit to the data than a linear func 

(Ffl, 17] = 2.76, P = .ll). The cubic function had an inflection a; 

ordinate value around 0.08 mg/L. Therefore, the data were. 

lyzed further to confirm whether there was a difference in 

association of lead levels in hyperactives and siblings above; 

below this level. Hyperactive children were divided between th 

with lead values above and those at or below 0.08 mg/L. Tat 

presents these data. A higher lead level in the hyperactive c: 

was found almost exclusively in the pairs where the hyperat. 

child's lead level was above 0.08 mg/L (Fig 2). 

As in the group analysis, differences in sex distribution ir.. 

hyperactive and sibling pairs could confound the association of!: 

levels and hyperactivity. The number of hyperactive girls (X= 

was too small to enable meaningful examination of this issue in -

20 matched hyperactive children. Among the siblings, mean leofthe 11 boys were identical to those ofthe nine girls (O.O8±0.i0.08 i 0.06 mg/L, respectively). Again, this result suggests tha: 

least for normal children, gender does not affect lead accumulate: 

Although a contrast between learning-disabled children •: 

their siblings was not a primary goal ofthe study, we examined!:. 

burden in learning-disabled children paired with their siblc 

Only five pairs could be generated. Every learning-disabled d 

had a higher lead level than his or her sibling. The differe::-

between the groups did not reach significance (0.21:1. 

v 0.08±0.03 mg/L, respectively; «[4] = 2.41, F = .07; sign it 

Arch Gen Psychiatry—Vol 40, Aug 1983 Lead and Hyperactivity—Gittelman & Eske:; 
P.6 

. siblings. jL, 

rnificantly-' 

'.he groups': 

igniffcantlyr 

tbles in the 

ntly nega- y 

.ower level*: 

! was found" 

led group 

' lead leveb 

\ipensity tol 

boys in tisel 

•nces. There-I 

•,irls in ea<A! 

..c 16 female-; 

-0.05 mg/I. 

..ie boys ani] 

cabled groaj! 

O.U±0.08t! 

..ing-disabla 

'[29]=-1.0V 

•a with onei| 

n one sibling 

.- comparisal 

,isties of tht] 

. there we.t| 

(x2(17)=4.J,'. 

• are shown aj 

higher meaj 

P = .02). The 

:!iffer signifr 

• 55% of tie 

• i levels in tte 

child aga 

ihe hyper 

Iheir sibling! 

notably, ba 

.-.ear functus 

•flection ati 

.it a were ; 

..rence in > 

.. 4S above aa'fl 

ietween tho 

ng/L. Table sj 

-,tractive chfitl 

o hyperacti 

•ibution in t 

•ciation of le 

s girls (N= 

his issue int 

„s, mean level 

.; (0.08 ± 0.04 ii' 

.s'geststhat,« 

: accumulate 

i children 

examined le 

their sibling 

.-disabled civ 

he differena 

:e (0.21 ±0.3 

.07; sign 

Table 6.—Relationship Between Lead Levels and 

Perinatal Complications in Hyperactive Children 

Lead, mg/L 

Presence of Complication N Mean SD t • P 

Pregnancy 

Ves 52 0.12 0.08 

14 0.08 0.03 

1.49 NS 

Labor and delivery 

Yes 14 0.07 0.03 

36 0.11 0.08 

•1.73 NS 

Neonatal 

Yes 26 0.10 0.06 

NO 31 0.11 0.09 

-0.36 NS 

Table 7.—Relationship of Lead Levels and Severity of 

Perinatal Complications 

Correlation With Lead Level 

Severity-Weighted History 

Pregnancy .37 64 .002 

labor and delivery -.21 48 NS 

Neonatal -.0 2 55 NS 

Table 8.—Examples of Perinatal Histories Rated Clearly 

Abnormal, Borderline, and Unremarkable 

Clearly Abnormal 

Premature rupture of membranes; oxygen given for 2 min 

" Mother had several miscarriages before conception 

. Toxemia 

, Infection during first trimester 

• HighBP 

Apgar score of 5 or 6 

Weight gain of >20.5 kg 

;..• High BP 

^ Apgar score of 2 

Delay in breathing 

Borderline Abnormal 

Cord around neck; baby otherwise healthy 

Emergency cesarean because of child's position 

Apgar score of 7 or 8 

. Precipitate labor, membranes ruptured 24-48 hr before delivery 

Severe stress during pregnancy 

Vomiting throughout pregnancy 

Mother in poor health 

Unremarkable 

Routine cesarean 

Mother >40 yr old (no other findings) 

X-ray film during pregnancy 

Miscarriages before this birth 

Difficulty conceiving 

Weight gain of >20.5 kg; no health problems 

Initial abnormality of fetus presentation; 

self-corrected during labor 

=.06). These results may have been confounded by age, since the 

ng-disabled children tended to be younger than their siblings 

?=.07). (These data are presented, in spite of the very small 

pie size, for possible heuristic interest.) 

Relationship Between Lead Levels and 

Severity of Illness 

^Nonsignificant correlations were obtained between lead level 

I hyperactivity factor scores (r[101] =. 10) and severity of illness 

JOI]=.00). 

Table 9.—Mean Lead Levels in Children With Abnormal, 

Borderline, and Unremarkable Perinatal Complications 

Perinatal Complications 

Clearly 

Abnormal 

(N = 21) 

Borderline 

(N = 29) 

Absent 

(N = 23) 

Lead, mg/L 

Mean *SD * 0.12 = 0.09 0.10 = 0.05 0.09 = 0.07 

Range 0.06-0.45 0.03-0.24 0.04-0.38 

*F(2,70) = .79, P=.46. 

Table 10.—Prevalence of Toxic Lead Levels Among 

Children With Abnormal, Borderline, and Unremarkable 

Perinatal Histories* 

Perinatal History 

Abnormal 

Borderline 

Unremarkable 

No. Of 

Children 

Lead Level 

N >0.08 mg/L 

21 15 

29 20 

23 11 

Lead Level 

s0.08 mg/L 

6 

9 

12 

'Overall: x2(2) = 3.31, not significant; abnormal plus borderline v unremarkable: x2

(1) = 331, P<.10; abnormal v borderline plus unremarkable: 

X

Z

(1) = 0.73, not significant. 

tions. The mean lead levels of hyperactive children without any 

pregnancy, labor and delivery, and neonatal complications and 

those with at least one complication did not differ significantly 

(Table 6). 

The association between lead level and mean severity score ofthe 

perinatal complications was examined (Tables 1 and 7). Children 

with greater mean severity scores of pregnancy complications were 

more likely to have higher lead levels. Neither mean severity score 

of labor and delivery complications nor the mean of neonatal 

condition was significantly associated with lead level. 

Socioeconomic status was not correlated significantly with lead 

levels in the hyperactive children (r[98] =. 15, P =. 13) or with mean 

severity of pregnancy complications (rf62] = .04), labor and delivery complications (r[46]=.03), or neonatal condition (r[53] = .08). 

Nevertheless, the data were reanalyzed, partialing out SES scores 

to estimate if a confound had been introduced in. the correlation 

between lead levels and perinatal factors. The correlations between lead levels and mean severity of perinatal complications 

generated by the partialing and by the Pearson correlation techniques were identical. 

The perinatal histories of 21 hyperactive children were categorized as clearly abnormal, 29 as borderline abnormal, and 23 as 

unremarkable. Examples of perinatal histories judged as clearly 

abnormal, borderline, and unremarkable (although some abnormality was reported) are shown in Table 8. Of the 21 mothers • 

considered to have clearly abnormal pregnancy histories, ten had 

toxemia during pregnancy. 

As shown in Table 9, lead levels of hyperactive children with 

clearly abnormal, borderline, or unremarkable perinatal histories 

did not differ significantly (F[2,70] = 0.79, P = .46). 

In addition, we examined whether children with clearly abnormal, borderline, and unremarkable perinatal histories were distributed differentially above and below '"toxic" lead levels. Table 10 

presents these data. A nonsignificantly higher proportion of 

children with abnormal prenatal histories (clear and borderline 

abnormalities) had toxic lead levels compared with children with 

normal perinatal histories (x2fl] = 3.31, P<.10). 

Relationship Between Lead Levels 

and Cognitive Test Performance 

in Hyperactives 

Age was partialed out of those tests not already age standardized, ie, GOR test, VMI test, and paired-associate test. 

A significant relationship was observed between SES and the 
P.7 

1 

i 

• 

WISC full and verbal IQs (rf 100]= - .31. P<.01). Nu other neuropsychological measure correlated with SES. 

As Table 11 indicates, lead levels did not correlate significantly 

with WISC IQ scores when SES was controlled, although children 

with lower IQs tended to have higher lead levels. (Significant 

correlations of lead with WISC full-scale IQ [r=.19. ." = .05] and 

verbal IQ fr=.20, F = .05] were obtained when SES was not 

partialed out.) None of the achievement test scores was significantly associated with lead levels. There was a trend between the 

WRAT reading level and lead levels, indicating that poor readers 

tended to have higher lead values (r[100] = - . 16, P =. 10). 

COMMENT 

This study failed to find higher lead levels in a large group 

of hyperactive children when compared with normal children. Yet, the results cannot be construed as altogether 

negative. We found a trend for a greater proportion of 

hyperactive children than normals to have lead levels above 

0.08 mg/L (P = .06), and hyperactive children had significantly higher lead levels than their own siblings (P = .02). 

Thus;, lead levels may be associated with hyperactivity in 

middle-class children. However, the association is weak. Its 

detection required the study of genetically related groups 

that provided inherent controls for a multitude of environmental factors, such as housing, neighborhood of residence, 

and social class. 

We found no clear-cut relationship between lead levels 

and. cognitive performance of the hyperactive children. 

Correlation coefficients were all in the expected direction, 

indicating that higher lead values were slightly associated 

with worse performance. In spite ofthe weak association of 

lead, levels and IQ, the consistency ofthe results in different 

populations3"

5

 suggests that the detrimental effects of lowlevel lead exposure, though minimal, cannot be entirely discounted. 

Comparison With Previous Findings 

This study was designed to replicate previous observations by David and co-workers"1

" of elevated urine lead 

levels in hyperactive children, especially in those children 

without any other known cause for their hyperactivity. Our 

data give support to their observation that a level exceeding 

0.03 mg/L may represent a relatively toxic urine lead level, 

that is, we found an inflection at that value in the distribution of lead levels of hyperactives and their siblings (Fig 2). 

Other results, however, are not consistent with David and 

colleagues'; we failed to find a significant elevation of lead 

levels in hyperactive children, except when paired with 

their siblings; we found only a trend for hyperactive children to have toxic lead levels (>0.08 mg/L); and lead levels 

and perinatal insult were not negatively associated in our 

hyperactive sample. 

The techniques for assessing lead level were identical to 

those used by David and co-workers and therefore cannot 

account for differences in the results. The two studies, however, differed in racial composition, age ofthe sample, diagnostic criteria employed, and the manner in which perinatal 

information was obtained. 

Race.—David and colleagues' sample was black and 

lower class; ours was mostly white and middle class. It" is 

very unlikely, however, that lead exposure interacts with 

race to produce hyperactive behavior in only one racial 

group. 

Diagnostic Criteria.—Our sample was selected for research purposes, with systematic evaluations and objective 

diagnostic criteria. The very high rate of clinical response to 

methylphenidate in the hyperactive children in the present 

study (80% to 90% improvement with the drug, and only 

15% with placebo12) indirectly confirms the accuracy of the 

diagnosis. Although David et al also used objective criteria, 

832 Arch Gen Psychiatry—Vol 40, Aug 1983 

Table 11.—Correlations of Lead Levels and 

Neuropsychological Performance in Hyperactive 

Children 

Wechsler Intelligence 

Scale for Children 

Verbal IQ 

Performance IQ 

Full-scale IQ 

Wide Range Achievement 

Test (standard score) 

Reading 

Arithmetic 

Spelling 

Gray Oral Reading Test 

(grade level) 

Paired-associate 

learning test (trials) 

Visual Sequential 

Memory Test 

Visual Motor 

Integration 

(Beery-Buktenica) 

Test mental age, yr 

N 

102 

102 

102 

102 

100 

100 

100 

79 

689 

97 

Score 

Mean 

103.3 

101.9 

103.0 

98.8 

94.8 

93.6 

2.7 

7.7 

19.6 

6.8 

SD 

13.4 

11.8 

11.4 

14.0 

9.5 

10.6 

1.9 

3.3 

4.5 

1.4 

Correlation 

With 

Lead Level 

r P 

-.16* 1C 

- .08* NS 

-.16* .K 

-.16 .K 

- .02 NS 

-.15 N ; 

-.12f N: 

- .06t NS 

-.15 NS 

-.12 t NS 

•Socioeconomic status was partialed out ot the correlation. 

fPartial correlations controlling for age. 

there was no such confirmation of the diagnosis. 

Age.—The children in our study were older than theDavid and colleagues'. Older children had lower che!. 

lead levels, probably because the same dose of chela-' 

agent was used regardless of weight. A uniform dose v< 

chelate more lead from smaller individuals, leading r. 

artifactual negative relationship between lead levels 

age. 

Since we found that lead levels were negatively correi. 

with age, the lead levels ofthe somewhat older hyperai 

children in our study (9.8 ±2.8 years) would be expt. 

to be lower than those of David and colleagues (7.7 ye; 

as was found. The magnitude of this difference, howt 

was a small one, about 25% of the SD reported in 

vid and co-workers' hyperactive sample (0.10 ±0.0 

0.14 ±0.14 mg/L, respectively). 

In the present study, the hyperactive group did not c 

significantly in age from the controls; age discrepam 

therefore, do not appear sufficient to explain the lav 

significant differences in lead levels between groups ii: 

investigation. 

Perinatal Histories.—Unlike David et al, we us 

structured questionnaire and where possible examined 

pital records. Perinatal histories were blindly coded. S 

David and co-workers relied exclusively on what seerm 

be ah unstructured medical intake interview, the histc: 

complications may have been underestimated and i\ 

bias may play a role in the results. In fact, 78% o; 

hyperactive children in the earlier study9 of David et a; 

50% of the children in the later larger study10 had histc 

negative for perinatal insult; only 19% ofthe hyperactiv 

our study, however, had no perinatal complication. 

The evaluation of perinatal histories presents difficu! 

It may not be possible to generate a clear-cut, valid estir. 

of perinatal risk. Unfortunately, there is not an a j. 

approach for ranking severity of perinatal insult that * 

reflect impact on neurodevelopment. Only the very extr 

Lead and Hyperactivity—Gittelman & Esk; 
nr—tiiiura 

Nation' 

.Vith 

•j Level 

,'t NS 

5T NS • 

'2t NS 

s are unequivocal for a determination of abnormality, 

as very low Apgar scores. 

Association of Lead Levels With Hyperactivity 

i indeed, lead levels are associated with hyperactivity, 

question arises as to the nature of this relationship. 

on their finding that children without any other 

cause of hyperactivity had higher lead levels than 

Js, David et al hypothesized that lead plays an 

ogicrole in hyperactivity. An equally plausible hypothimplies that increased lead accumulation may result 

hyperactivity: children with higher activity levels may 

emore air, "kick up" more dust, or be more apt to dispica (eating paint chips or dirt). The association of lead 

with hyperactivity, however, may be neither cause 

affect. Lead levels may be related to hyperactivity only 

gh their association with a third variable. 

,d as a Cause of Hyperactivity.—Unlike David et al, 

found no evidence to suggest that lead played an 

logic role in hyperactive children without a history of 

ital complications. Instead, children with prenatal 

iications were more likely to have higher lead levels. 

result is consistent with that of Winneke et al,~ who 

found a slightly higher prevalence of perinatal risk 

NS •> r s '

n a group of children with high tooth lead levels. 

lead were a cause of hyperactivity, we might expect 

severity of hyperactivity would be associated with lead 

i; however, no association was found. Our group conof relatively severe hyperactive children. It is conJe that different results would emerge if children with 

fer range of hyperactivity were studied. 

also found considerable overlap in the lead values of 

' tractive children and their normal siblings. Conse-

. itiy, "high" lead levels cannot be construed as sufficient 

.1 thoses lyperactive disorders to occur. This is hardly surprischelata jftis most likely that hyperactivity is multidetermined; 

ihelaoq result, one would not expect a single factor, such as lead 

•se

 vv0

 • tare, to be its sole or major cause. 

ngtoa ereased Lead Levels Resulting From Hyperactiv-

•vels anj :jf children by nature of being more active are exposed 

! reater amounts of ambient lead, then hyperactive 

.•re^aa ^n should have had higher lead levels than the group of 

ng-disabled children who were not hyperactive. This 

otfound to be the case: the mean, range, and distribu-

.' the lead levels of learning-disabled children were 

["similar to those of hyperactive children, and both 

shad levels somewhat higher than those ofthe normal 

s. It may be that lead contributes, in part, to a diverf developmental disorders. Unfortunately, the scarrfnormal siblings ofthe learning-disabled group did not 

fus to investigate this issue fully. 

Jternative Relationship.—Elevated lead levels may i 

her cause nor effect of hyperactivity; instead, hyper-] 

/and lead levels may be related through their associJ'with a third factor. Perinatal stress may leave the child 

able to other factors that could be detrimental to denent. For example, the impaired organism may be 

|le to metabolize or excrete lead. The finding that sef of pregnancy complications was positively associated 

lead levels is consistent with this hypothesis. 

Source of Lead Exposure 

itory of pica may have been more common among the 

:tive children than their siblings. We could not 

this information. It is most unlikely that pica was a 

in our groups since all children lived in post-World 

housing in suburbs where dilapidated walls with lead 

ips, a major source of lead intoxication, are virtulexistent (pica of leaded dirt may still be a source). 

in which the children lived, however, is congested 

Eska S1 Psychiatry—Vol 40, Aug 1983 

e use 

lined! 

with automobile traffic, and air lead content was probably 

one of the highest in the United States at the time of the 

study. 

The significant correlation of lead levels of hyperactive 

children and their siblings suggests that environmental exposure or shared genetic inability to excrete lead are primary factors in lead accumulation. The question remains 

why hyperactive children had higher lead levels than their 

siblings, given that the water, air, and home environment 

vvere the same for these children. i 

The findings suggest that lead is not salient, but not 

negligible, as a contributor to hyperactivity and possibly 

learning disability, in nondisadvantaged children. Nevertheless, whether lead puts children at risk for developmental disorders, albeit a small one, remains an important 

public health issue. 

This investigation was supported in part by grants MH18579 from the 

Public Health Service and 5-T32-ES7086 from the National Institute of 

Environmental Health Sciences. 

Donald F. Klein, MD, provided comments. Beth Landa, PhD, performed 

data analyses. Millie Heimlich coordinated the data collection. Bernard 

Davidow. MD, and the Department of Health, City of New York, performed 

the urinalyses. 

References 

1. Byers RK, Lord EE: Late effects of lead poisoning on mental 

development. Am J Dis Child 1943;66:471-494. 

2. Chisolm JJ, Kaplan E: Lead poisoning in childhood: Comprehensive 

management and prevention. J Pediatr 1968,73:942-950. 

3. De la Burde B, Choate MS: Early asymptomatic lead exposure and 

development at school age. J Pediatr 1975;87:638-642. 

4. Landrigan PJ, Whitworth KH, Baloh RW, et al: Neuropsychological 

dysfunction in children with chronic low-level lead absorption. Lancet 

1975;2:70S-712. 

5. Perino J, Ernhardt CB: The relation of subclinical lead level to 

cognitive and sensorimotor impairment in black preschoolers. J Learning 

Disabil 1974;7:26-30. 

6. Pihl RO, Parkes M: Hair element content in learning disabled children. 

Science 1977;198:204-206. 

7. Baloh R, Sturm R, Green B, et al: Neuropsychological effects of 

chronic asymptomatic increased iead absorption. Arch Neurol 1975;32:326-

330. 

8. Needleman HL, Gunnoe C, Leviton A, et al: Deficits in psychological 

.' and classroom performance of children with elevated dentine lead levels. 

, N EnglJ Med 1979;300:689-695. 

9. D;.vid O, Clark J, Voeller K: Lead and hyperactivity. Lancet 1972:2: 

900-903. 

10. David OJ, Hoffman SP, Sverd J, et al: Lead and hyperactivity: Lead 

levels among hyperactive children. J Abnonn Child Psychol 1977;5:405-

, 416. 

I 11. Rutter M: Raised lead levels and impaired cognitive/behavioural 

functioning: A review of the evidence. Dec Med Child Neurol 1980; 

, 22(suppl):l-26. 

\ 12. Gittelman-Klein R, Klein DF, Katz S, et al: Comparative effects of 

I methylphenidate and thioridazine in hyperkinetic children. Arch Gen 

I Psychiatry 1976;33:1217-1231. 

I 13. Gittelman R, Abikoff H, Pollack E, et al: A controlled trial of behavior 

modification and methylphenidate in hyperactive children, in Whalen C, 

Henker B: Hyperactive Children. New Vork, Academic Press Inc, 1980, 

pp 221-243. 

14. Gittelman R. Feingold I: Efficacy of remediation in reading disabled 

children. J Child Psychol Psychiatry 1983:24:167-191. 

15. Cor.ners CK: A teacher rating scale for use in drug studies with 

children. Ain J Psychiatry 1969;126:152-156. 

16. Werry J: Hyperactivity, in Costello CG (ed): Symptoms of Psychopathology. New York, John Wiley & Sons Inc, 1970, pp 397-417. 

17. Diagnostic and Statistical Manual of Mental Disorders, ed 2. 

Washington, DC, American Psychiatric Association, 1968. 

18. Wender P: Minimal Brain Dysfunction in Children. New York, John 

Wiley & Sons Inc, 1971. 

19. Halperin JM. Gittelman R: Do hyperactive children and their siblings 

differ in IQ and academic achievement? Psychiatr Res 1982;6:253-258. 

20. Woerner MG, Pollack M, Klein DF: Pregnancy and birth complications in schizophrenics, personality disorders, and their siblings. Acta 

Psychiatr Scand 1973:49:712-731. 

21. Hollingshead AB, Redlich FC: Social Class and Mental Illness: A 

Community Study. New York, John Wiley & Sons Inc, 1958. 

22. Winneke GA, Hrdina KG, Broekhaus A: Neuropsychological studies 

in children with elevated tooth-lead concentrations: I. Pilot Study. Int Arch 

Occup Environ Health 1982;51:169-183. 

Lead and Hyperactivity—Gittelman & Eskenazi 833 

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