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DOCUXZKT REVIEW* FORM 

fltlt/Draft 

Ai r Qualit y Criteri a fo r Lead 

(Externa l Review Draft #1) 

aUturn to: 

Projec t Office r fo r Lead 

Environmental Criteri a and 

Assessment Office , U.S. 2Pi 

MD-S2 \ 

Research Triangl e Park, NC : 

ConsBcstcr/Organlzation/Address * 

Herbert L. Needlesran, M.D. 

Children's Hospital of Pittsburgh 

125 DeSoto Street 

Pittsburgh, PA 15213 

\ 

Chapter No./Title 

Chapter 12 

and^ 

Appendix 12 

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ECAC7TIC 

u 
P.3 

ECA O Critique, Needleman 

General Comments: The quality of the document varies widely. 

Some chapters are models of scholarsip and re-flective criticism, 

while others are tendentious, superficial and noncritical. The 

most egregious errors are in the most critical chapter. This is 

Chapter 12, where human health effects are evaluated. This 

discussion in no way comes up to the standard of the ether 

chapters. It is neither fair nor accurate. I shall concentrate 

on this chapter, because its content is so vital to the 

construction of a valid document that will withstand critical 

scrutiny and eventual testing in the courts. 

CHAPTER 12 

section/ page / para / line Comments 

12.4.2/12-42/2/16 

"Some prospective longitudinal studies of the 

effects of lead on infants and young children are 

currently in progress, but the results are not 

yet available". This is incorrect. Ule have 

reported the results of our prospective studies 

.of prenatal exposure at 2 national scientific 

meetings (Society for Pediatric Research, and 

Society for Research in Child Development). Both 

were reported in early 1983 before the EPA 

deadline. Both of these studies were 

peer-reviewed, and the abstracts were published 

in a refereed journal. Pediatric Research 

17:179a, 1983; 17:1281a, 1983. These studies 

showed a dose-dependent relationship between lead 

in umbilical cord blood and minor congenital 

anomalies, and later developmental status in 

infants, controlling for relevant covar i ates . 

They are the first publications in the human 

literature on the subject and should be cited 

here. The congenital anomalies paper is in 

pness, JAMA. 

12.4.2.1.2/12-48/ The studies of E.Baker et al on the psychiatric 

symptoms of lead workers at low dose^Acta 

Psychiatrica Scandinavia, 1982) are not mentioned 

in this section. 

12.4.2.2 This section is inadaequate in its discussion of the 

definition of encephalopathy. Older definitions 

of encephalopathy implied brain edema and 

hemorraoe. These findinos were associated with 

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V 
P.4 

ECAD C r i 11 que , Needleman 

elevations of blood lead levels above 88ug/dl. If 

lead exposure at lower dose results in decreased 

cognitive or behavioral adaptation, the organ 

which mediates this deleterious change must "be 

the brain. The changes in brain anatomy which 

accompany these alterations are pathological, 

even if not accompanied by changes found en light 

microscopy. Modern pathologists have shifted 

their locus of investigation down from changes at 

level of light microscopy to those identifiable 

only by electron microscopy or chemical 

techniques. A modern treatment of this issue 

requires a modern definition of encepa 1 opa thy, 

congruent with the facts. All changes in brain 

function necessarily imply brain disorder, and 

pathological changes of' the brain at any level 

are necessarily the ground substance of 

encephalopathy. 

12.4.2.2.2.1/12-60/12/ 22 

It i s unscientific to assign a 1 ower level to the 

blood leads in Burde's study sample on the basis 

of Betts' paper for this reason! The diagnosis of 

lead lines varies widely among individuals and 

institutions. One cannot validly assign a blood 

value to Burde's subjects without comparing films 

from both samples to calibrate the relative 

sensitivity of each group's diagnostic criteria. 

This criticism, it will be noted, has been 

applied by authors of the draft document to the 

use of other non-standardized instruments in 

other parts of the document. 

12.4.2.2.2.1/ 12-62/ 2 

The review of Ernhart's second paper shoulo state 

that after multivariate control of covariates, 

significant differences favoring the low lead 

group were found en 4 of 5 subtests of the 

McCarthy Scales. It is obligatory that the 

Criteria Document render a veridical review of 

the primary papers, and not rely on the 

conclusions of the neurobehavioral parrel, who 

were not a part of the total discussion of tnis 

subject. 

12.4.2.2.2.1 / 12-64/2 / 8 

The summary of the repor t of Needleman e t al 

comparin g IQ distribution s in hig h and iow lea d 

groups showed tha t the ris k of havin g an IQ < 88 

was increase d almos t 4-fol d in associatio n wit h 
ECAO Critique, Needleman * 

high tooth lead levels. This should be mentioned 

in this section. This graph should be published 

in th i s sect ion. 

12.4.2.2.2.1/ 12-65/ 1/ 4 

In other communications to EPA/ORD, I have 

demonstrated that the Neurobehavioral Panel 

appointed to review my work and that of Dr. 

Ernhart committed at least 12 errors of fact in 

their evaluation of my studies. The direction of 

all of these errors was to weaken the conclusions 

drawn by my studies. Many of theses errors 

persisted in the face of repeated attempts by me 

to correct them. Although most of the errors 

which appeared in the August 1983 draft of the 

Panel report were extirpated in the November 1983 

version, the conclusions which relied on these 

errors were allowed to stand. The panels 

conclusions, which were not subject to peer 

review, _s±i.nul.d nnl ja_p.p.e.___c ID lh£ LLII&LI*. j_l__.___i-l. 

12.4.2.2.2.1/ 12-65/ 3/ 

The study ef McBride et al<1982) employed as the 

principal outcome measure, a test that I had 

shown in 1975 to be insensitive to the effects of 

low level lead . exposure: the Peabody .Picture 

Vocabulary Test (Needleman, EPA Final Report 

1976). 

12.4.2.2.2.1/ 12-66/2 

The ECAO has been inconsistent in its application 

of the ground rules applied to studies admitted 

to the Draft Criteria Document. The Executive 

Summary states that the scientific literature has 

been reviewed up to June 1983. This paper was not 

available to the scientific community until its 

publication until October 1983. Sufficient time 

has not been available to evaluate it thoroughly 

by the scientific community. A quick analysis 

reveals that the conclusions drawn by the authors 

may well be incorrect, and that this pacer 

supports the position that lead at low dose may 

affect development. Among the criticisms which 

require that the paper's conclusions be 

sceptically received are: The authors used whole 

tooth levels, a technique which may lead to 

misc1 assification of subjects. They employed a 

large battery of tests, but in reporting their 

results, only state that they were net 

significant; they do not give actual p-values. 

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P.6 

ECAO Critique, Needleman 

(I have written to R. Lansdown and requested 

them) The differences between groups was of the 

same order of magnitude as those reported by 

Needleman et al, before control of covariates, 

and the reduction in differences was about the 

same. This finding has led Michael Rutter to 

conclude that the study supports conclusion that 

lead at these doses is neurotoxic(Rutter, 1981, 

1982). Ha.cue.a_.ls aa.ae.fc i_& aol la aalal-*. aad has ao 

ala.cc la Ihe. docua_aal«. 

12.4.2.2.2.1/ 12-68/ 

It is not clear why the document concludes that 

the difference in teacher's rating found by Yule 

et al on the Needleman scale reflect attention 

deficits rather than conduct disorder. It is 

true that the rating and the 

correlated, but that does 

behavioral effects were less 

studies of Attention Deficit 

IQ's were 

not mean that the 

important. Followup 

Disorder have shown 

that increases in the incidence of conduct 

disorders are frequently associated with this 

syndrome. Yule's graph o f teachers' ratings 

should be published here. 

12.4,2.2.2.1/12-68/ 

Ui nr^kfr'ft *tnrii»s ^re inadequately treated in 

this discussion. They also support the leaddevelopment relationship. The bias of the writer 

is apparent in the treatment of Winneke's work. 

12.4.2.2.2.1/12-69 

The summary paragraph on this page betrays 

naivete about epidemiological studies. No 

epidemiological study is without flaw. Nor can 

causality be demonstrated empirically- either in 

the field or in the experimental laboratory. It 

strains the bounds of critical thinking to say 

that because ef this, no conclusions can be drawn 

about the causes of deficit in relation to lead 

at low dose. This chapter does not go this far., 

but by its cautionary tone, provides useful and 

quotable material to. those who would take this 

position. Investigators in this area, ana 

educated readers know the limitations of their 

craft, and do not require that the limitations of 

these studies be repeatedly brought to their 

at tent i on. 

12.4.2.2.2.5 12/71/2 

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P.7 

ECAO Critique, Needleman 

It is difficult to understand why the study of 

Burchfiel et al is dismissed so summarily. The 

writers of the chapter state that because 

individual dentine l**d levels were not 

furnished, it is impossible to estimate 

lead-exposure levels associated with the observed 

EEG effects. They ask more from the study than 

it was designed to do. The study was designed to 

address this question: Does lead exposure below 

that which produces clinical symptoms produce 

electroencephalographic changes? The medical 

I'i terature prior to this publication was uniform 

in concluding that EEC changes were not seen if 

clinical encephalopathy was not observed. This 

paper is the first(and only)report to dispute 

this statement, and deserves mention in this 

context. Inferences can readily be made about 

the exposure levels experienced by subjects in 

this study. The exposed group came from the 

highest decile for dentine lead, and that their 

mean blood lead level, four years prior to having 

their EEC's evaluated, was 34" ug/dl. In contrast 

to the intriguing findings of the Otto study, 

whose clinical significance is not clear, the 

clinical relevance of the changes in . the 

Burchfiel study are obvious. 

12.6.1.4. 12/152/3 

The effects of lead on the developing human. 

This section contains no mention of the studies 

by Needleman et al dealing wwhich show that 

increasing umbilical cord blood lead levels are 

associated with increased risk for minor 

congenital malformations and decreased 

developmental scores on the Bayley ScalesXPed 

Res.17:1281a,1983, Ped Res.17:179a,1983,and JAMA. 

in press). In both studies, control of relevant 

covariates was achieved, and significant lead 

effects on birth outcome and subsequent 

development was demonstrated. 

APPENDIX 12-C: General Comments 

This appendix appeared in two versions, one issued in August, 

1983, and the second in November,1983. The first version was 

issued with 12 rather obvious errors concerning the studies of my 

group. All of these were biased to diminish the conclusions 

drawn by my group about the 1ead-neurobehavioral relationship. 

These errors were committed even though I had corrected many of 

them, in writing to the ECAO director, prior to the draft's 

«.• 
P.8 

ECA O Critique , Needlema n 

i 

issue . The y reache d prin t I beeaus e di d ir»©t B as 

agreed, receive a prepublieati©n draft 4or peview. 

w as withdrawn when I Seek str©ng exeeptien t© its orrerss 

but net all ©f th© orrers were eaeisedo Man y ©f the conclusions 

drawn from the err©rs were all©wed t© -stand. 

prev i ©ugly 

This draft 

many, 

yhi1e th© member s ©f the panel are unquestionably experienced 

in the fields ©f biometries, devel©pmental psyehelegy, and 

pathelegy, it is worthy ©f merit i©n that n© member ©f the panel 

in the relevant disciplines ©f field 

texieelogy. Thi s deficiency becomes 

with eare the canons they apply t© the 

lead effects at low dose. A-fter 

be encounterd after 

that 

appears to have experience 

epidemiology ©r behavioral 

apparent when ©ne .examines 

enterprise ©f evaluating 

reviewing the types ©f finding whieh could 

studying this problem, the panel concludes 

°...ne matter hew earefully designed and executed, 

erosssecti©nal studies ef relationships between Pb and 

cognitive functioning ar© not able t© yield definitive 

conclusions regarding the influence ©f low-level Pb 

exposures on human cognitive functioning... At best, 

such cross-sectienal studies may yield ©v 

suggestive of effects of low~l@vel Pb exposures 

would need to be confirmed 

definitive research designs° 0 

by studies using 

i dene© 

wh i eh 

more 

This statement, contained in the introduction te the 

report, predicts their later judgements. They infer th 

studies published to date are cross-sectional, no "defi 

conclusions can be drawn from the current body of sei 

information en human effects ef lead at low dose. The 

would have it that w© must wait , 6 years and 17 papers af 

first air lead standard, for a forward study to allow def 

conclusions to be drawn. Since only one forward studyvm 

been published to date, and since the panel and ECAO h 

reviewed it, th© reader could predict with 

panel will end with an equivocal conclusion, 

almost all panels of this nature do. with 

studies. Thi s type of stereotypic behavior 

earlier to many such environmental questions, 

accuracy th 

They cone Iu 

a cal 1 f o 

h as been 

most nota 

cr i t i e i sms 

asbestos. 

.of studies of the risks ef exposure to tebae 

panel's 

at al 1 

n i t i v e " 

e n t i f i c 

panel 

ter the 

i n i t i v e 

i ne)ha s 

as not 

at the 

de. as 

r more 

appli ed 

b 1 y in 

co and 

Epidemiolgists are aware of the limitations of their craft0 and 

th© inability of their exertions to yield "definitive" proof of 

the relationships under study. They set more realistic goals for 

themselves, and expect to add incremental information to the 

clarification of the phenomena under examination. They do not 

tax themselves with the responsibiIty of providing definitive 

conclusions £.vl s^a&^ls about the relationships they investigate, 

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P.9 

ECAO Critique, Needleman 

but hope to paint part of a picture, which if consistent and 

coherent with other studies from the field and laboratory, permit 

judgements to be made about the causal (that is to saypredictable and dependable) relationships between the events 

under examination. The inabilty of empirical studies to prove 

causal relationships was clearly stated by Hume, and.one of the 

members of the pane I(Kupper), in recognition of this, states 

"Inferring that a given factor is a risk factor for a 

disease is a v*ry complex process involving many 

uncertainties. There are several reasons for believing 

that causal inference depends on more than a single 

test of a hypothesis based on one set of 

observations....Final1y, we cannot draw a definitive 

conclusion from the results of one analytical test 

because of the limitations of induction discussed 

above." 

Despite this, the panel report uses this acknowledged limitation 

to diminish the impact of the two studies they cite, each 

examined in isolation. The panel nowhere givrs attention to the 

coherence and consistency of the recent studies of lead and 

children. It does not trouble itself to collate the studies 

which bear on this point. The report treats each study as if it 

exists in a cognitive vacuum, and' ignores the similarities in 

difference in IQ scores between high and low lead groups in 

studies conducted in three different countries. They similarly 

ignore the intriguing finding that all of these studies show the 

same amount of difference(about 4-6 points) on IQ scores before 

controlling for covariates, and that after adjusting, the 

reduction is about the same in all studies(3-4 points). At no 

point in their critique do they recognize the correspondence 

between the animal studies and the epidemiological 

investigations. Specific comments on Appendix 12-C 

Page 7: 

The document does not indicate that Ernhart neglected to 

control socioeconomic status in either the first investigation 

(1974 or the follow-up study (1981). The only comment on this 

egregious omission is oblique: "It is not known whether a finer 

SES scale would have resulted in greater relations between SES 

and other variables in the study than those related by Perrino 

(1973)'. The neurobehavioral panel states that, "Maternal 

occupation was recorded from clinic records employing a 1956 

census classification that was 4D.ad__j_ij_1.a_l.__ ±& J±L11£I:£JL,±12L±£ _ymnr..g 

jur-b-an hl^cksl. temphasi s added] On careful reading, the original 

paper by Perrino and Ernhart is in conflict with this statement. 

It says:. "They [parents] ranged from _r_a.aa.QacE.* clecical wocLfccs* 

stilled aad uask_ille.d wock.acs lo se.C-__.xoe. wock.e.cs aad t__e.ii.ace. 

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P.10 

SCAO Critique, Needleman 

£.__.e_ip.i-i&lg>. Eemphasis added] Th© superficial attention ©f the 

panel t© the ©mission by ^orrin© and Ernhart ©f SES control 

stands in distinct eentrast t© the eritieisms ©f the work of 

Needleman,. ot al . In these eritieisms,, the Needleman study is 

faulted net fer neglecting t© e©ntr©l f©r SES, buS <{"©r using 

parental SES instead ©f parental odueati©n_ Since SES is a 

composite yariablo eempesed ©f odueati©n and ©eeupatien, the two 

faeters ean be expected t© be= and are°highly correlated. 

The panel ratifies the PQmeval ©f a

 D©utlier ° by Ernhart in an 

unpublished study, as appropriate methodology. This subject was 

removed from the analysis after being identified as having a 

severe decrease in intelligence. This retrospective removal of 

subjects does net withstand seientifie scrutiny. As X teld the 

working* p<%rty in North Carolina, the high dentine load level in 

the subject excluded by Ernhart was probably caused by dentinal 

hypertrophy secondary te the earie in that t©eth. It is not 

legitimate to exelude the subjeet, wh© was discovered because the 

IQ score was v<sr-y low, and then reconstruct a reason. According 

te Perrino's and Ernhart's original paper,

 DA1 I [subjects] were 

asymptomatic and had no known illness or history of conditions 

associated with intellectual impairment..iadditional1y, there 

were ne records ef previous hospitalisations for lead 

intoxication." It cannot be considered scientifically rigorous 

first to set up criteria to test a hypothesis and then, seme 

years later, when the conclusions drawn are net acceptable te the 

author, selectively remove a subjeet who initially met the 

criteria. Supporting this procedure does not testify to the 

panel's critical acuity. 

Page 14: 

The panel notes that reading test scores were obtained from 

many different tests, but concludes that the combination of 

multiple measures does not necessarily compromise the assessment 

of reading achievement. While this may bt true for estimation of 

an individual's achievement, it cannot be considered acceptable 

practice in a research effort. This would be one ef the first 

times that a research design would permit the merging of data 

from eleven^ different instruments across the sample size ef 

approximately 80, without establishing intertest reliability. 

When the panel turns to the studies of my group, it appears 

that a different level of critical stringency is employ^. In 

the first version of the panel's report, the panel, whose role 

was te assess the precision and validity of my work, committed at 

least 12 errors of fact and inference. These were called te the 

attention of Dr. Grant and the EPA in a letter of October 9 

(enclosed).. I will not repeat the documentation of these errors 

here. ' These errors were in the main removed from the second 

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P.11 

ECAO Critique, Needleman 

version of the panel's report, but the conclusions which were 

derived from them were allowed to stand. 

Page 29 Paragraph D 

The method of isolating dentine which I personally developed in 

Boston was quite simple, contrary to the panel's report. It 

involved the use of a small chisel and a copper mallet. The 

panel reiterates that this entails methodologic •kill. They go 

to state that it appears that a plus or minus 157. represents a 

reasonable specific estimate of the variability for dentine 

analysis. That i* correct. It is also correct that as stated on 

page 38, "greater variation exists among those individuals 

excluded". That is because greater variation was precisely the 

reason for their exclusion. 

Paragraph E 

While Shapiro and co-workers did report a better correlation of 

tooth/lead contrations per year, with either blood or EP 

contratiens, the coefficient of determination was extremely 

small. In paragraph 3, page 32, the two errors detected by the 

panel in calculation of parental IQ were corrected and the data 

reanalyzed. This is shown in table 1 of the appendix. No 

difference in the significance ef the IQ scores was found. In 

paragraph 4, the panel noted a higher proportion of discrepancies 

between verbal and performance IQ scores. We calculated the 

correlation between the verbal and performance IQ scores in our 

sample and found that they corresponded quite closely to those in 

the Wechsler manual. 

Page 33 I tern A 

The panel questions whether subjects would be reassigned 

because of the 15% variability in dentine lead analyses. It 

should be noted that the lb'/, variability is defined as acceptable 

by the Center fer Disease Control in its quality control for 

blood lead. There is no reason to believe that the variation 

would be biased and it is therefore reasonable to assume that 

reassignment due to variance in dentine lead levels would be 

random and unbiased across categories. If anything, this 

variance would bias the study l-ouiacd ±h£ null hxf,n±b££,l&m. 

Page 34 Item C 

This criticism simply does not correspond with the facts. The 

criteria for exclusion were clearly delineated, and we adhered to 

them. 

I tern D 

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P.12 

ECAO Critique, Needleman 

We have reanalyzed the data, using both age normed scores and 

raw scores and present them in the attached report. Our 

conclusions are sustained by this reanalysis. 

Item F 

The committee neglected to mention that 65 out of 66 outcome 

favored the low lead group, even if not at the level of .85. The 

possibility of this occurring under the null hypothesis is 

vanishingly small. This finding was reported in Lancet, 

September 11, 1982, and called to the committee's attention. 

I tern G 

When we did introduce age into the regression as a covariate 

and raw scores as an outcome variable, the relationship between 

lead and outcome was not materially altered. Introducing age 

into the regression against scaled scores caused a change in the 

sign ef coefficient of the age variable. This supports the 

assertion that it is undesirable to correct ..for age twice as 

quoted in the panel's report. 

Page 38 Comments on the Burchfiel Study Item C 

The panel asserts that because there is no definite dentine or 

blood lead levels reported for specific children, it is 

impossible to determine with any confidence the specific lead 

exposure. The study was not designed to determine specific lead 

exposure. Its goal was to assess whether "subclinical" lead 

exposure was asssociated with changes in function. An estimation 

of the blood lead levels in both groups is possible, however. 

The children in the high lead group'were in the 96th percentile 

for lead in Sommerville and Chelsea and their mean blood lead 

level tested four years prior to tooth shedding was 34 ug/dl. 

The referent group was children in the lowest 16th percentile for 

lead. Their mean blood lead level i.n 1974 was 24ug/dl . This is a 

straightforward analysis of variance design which has been used 

for decades in comparison of drug effects and toxic exposure. 

*.£*g* 39 1 tern D 

The comments of the panel on the 1982 Needleman report are 

incomplete. It is worthy of mention that the teacher's rating 

scale analysis in this sample, from a different city,shows a 

similar relationship between dentine lead and proportion of 

children receiving negative reports on each item. In addition, 

step-wise logistic regression controlling for covariates of 

relevance indicates that a relationship between lead and 

behavioral dysfunction was found. The reservations expressed by' 

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P.13 

ECAO Critique, Needleman 

the committee regarding the 1982 paper were similarly stated in 

the error-ridden earlier report of the committee. While the 

errors are extripated, the conclusions remain the same. The 

final statement of the committee that the cumulative frequency 

distribution curves in asymptomatic subjects is misleading is 

absolutely incorrect. While one of the subjects with clinical 

lead poisoning did have a high IQ, this finding is irrelevant to 

the presentation of distribution curves in asymptomatic 

subjects. This study, by a p.t_____atl design, excluded symptomatic 

subjects from data analysis. 

Page.40 Comment F 

It is difficult to understand these remarks. The panel states 

that an analysis of the relationship between teacher rating and 

lead level following adjustment for confounding variables was not 

reported. On the contrary, it was reported, and forms the major 

burden of the report to EPA. In this study, we reduced the 

outcome space by cluster analysis and then submitted the clusters 

to logistic regression analysis, entering relevant covariates 

into the model. This is clearly documented in.-the report to EPA. 

SUMMARY 

In summary, this appendix is remarkable in the uneveness of the 

criteria it applies to the two groups of studies. Although most 

of the errors identified by me in my letter to the director of 

ECAO are removed, the conclusions drawn are virtually unchanged. 

We recently reanalyzed the data in our study according to the 

criticisms of the panel, and present the results in the following 

pages. It is apparent that after reanalysis, the relationship 

between dentine lead level and neuropsychologic outcome (Wechsler 

full-scale and verbal IQ) remained as reported in our 1979 

paper. 

The output of this panel was foretold in the early pages of 

their report. The panel established criteria for establishing 

causality that no single epidemiological study could meet, and 

having done this, reject as flawed the studies they reviewed. 

The pertinent question to address to this panel's appendix is: 

"What evidence would they have found persuasive that lead at low 

dose is neurotoxic?" The application of wrongly placed 

epistemologic criteria, the numerous misinterpretations of my 

work, their refractoriness to correction, and their unwillingness 

or inability to view these studies in context suggest that no 

concatenation ©f studies would have altered their 

preconceptions.. 

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P.14 

APPENDIX to the ECAO CRITIQUE BY HERBERT NEEDLEMAN 

INTRODUCTION: The report of the ECAO panel on neurobehavioral 

studies raised some questions about the design and data analysis 

of the Boston study of low level lead exposure<Needleman et 

al,1979). That report was issued in two versions, August,1983 

and November, 1983. The criticisms raised may be summarized as 

follows: 1. That Fathers' Education should have been used as a 

covariate instead of Fathers' SES. 2. That errors in calculating 

Parent IQ could have biased our results. 3. That sampling 

procedures could have introduced bias, and that missing data 

points could have posed a validity problem. 4. That criteria 

used to define Pb exposure or to exclude subjects were arbitrary, 

and that different results could have been obtained by different 

methods. 5. That age should have beeen used as a covariate in 

the analysis instead of relying on age-normalized scores. 6. 

That the spread between Verbal and Performance scores within 

subjects was greater than expected. 7. That the teachers rating 

scores cannot be used as evidence for a lead-behavior effect 

because covariates were not controlled. '8..- That the use of 

analysis of variance model to compare extremes could 

overemphasize the difference between groups, and vitiates the 

utility of the study to determine dose-effect relationships. 9.. 

That the validity of classification of subjects 'by dentine lead 

is questionable. 

In j. letter to Lester Grant(Oct 7,1983), I responded te the 

many errors of fact and interpretation contained in the first 

draft of the panels report(Aug,1983). That response will not be 

repeated here. In this report, I attempt, to address primarily 

those questions of design and analysis made by the panel, and to 

evaluate their impact on the conclusions my colleagues and I orew 

in 1979 on the effects of lead at 1©w dose and neuropsychological 

function in children. 

In this presentation, for reasons of economy of time and funds, 

we concentrate on one outcome measure of major importance: the 

WISC-R IQ scores. The same analysis could be applied te the 

other outcome measures as well. 

- 1 -
P.15 

1 

CRITICISM AND RESPONSES 

1. Father's SES *hould have been replaced with fatherss 

education as a covariate. 

« We substituted father's education in the ANACOUA 

model (Table 1, Model 4)., and compared mean •cores, and F ratios. 

2. Mistakes in parent IQ calculation may have introduced 

bias into the analysis. 

* We corrected the two erroneous parent IQ 

scores(out of 158 subjects), and repeated the analysis(Table 1.Mode 

3. Exclusion of subjects for missing covariates 

could have biased the analysis. 

• We compared outcome measures on those subjects 

included and excluded because of missing variables, and tested 

significance by T-tests.(Table 2) 

4. Exclusions of subjects for possibly confounding 

variables, e.g., head injury, not being discharged with mother, 

may have biased results. 

« We regressed dentine lead level and covariates 

vs IQ for all subjects, for included subjects, and for excluded 

subjects, and examined the coefficients for lead and covariates. 

The theoretical reasons for .excluding subjects 

with such risk factors as head injury er perinatal distress from 

analysis are self evident. When we cross tabulated the 

categories for exclusion against lead levels, we found no 

noteworthy differences in distribution of lead levels between 

included and excluded subjects. Nevertheless, we examined the 

dose-response function for Pb and IQ, using a model of the 

f o.l 1 owi ng form: 

IO=a*ibX+dPb . + c D 

«_ *• • i 

e I I I'I I 

where X are covariates such as mothers' IQ, and D is a dummy 

variable that take on a value of 1 if exclusionary and 0 

otherwise. We repeated this analysis on the same data set, after 

removing those 16 cases who were identified as either having had 

lead intoxication, or been chelated. This was done because of 

concerns about multicol 1 inearity. Using multiple regression 

analysis, we tested the hypotheses that (1) the d coefficient 

maintained a negative sign when the previously excluded cases 

were included in the model, and (2) that the excluded cases were 

ha-rvd-led appropriately by testing that the coefficients .were 

negative. 

5. Age was improperly controlled. * We took both raw and 

standardized verbal and performance IQ scores, and regressed 

them, with age, lead and covariates, and then compared the 

coefficients for age and lead under both 

conditions-unstandardized and standardized dependent variables. 

The panel.suggested that the proper specification in the IQ . 

regression model should have the following form: 

- 2 -
P.16 

(1) (IQ - a « - * « Age)= b • b Age • d Pb 

e e i 1 

where a * - a « Age » age adjustment based upon national 

9

 1 

standards 

In the 1979 paper, Needleman et al estimated the following 

model: 

(2) (IQ -a « - a 

6 1 

We agree that equation 

oeneral form could be 

Age) «* b *d Pb 

e l 

(2) is a restricted form 

used. However we bei 

and that a more 

ieve that the 

fol1owi ng 

appl i c.abl e 

specifat ion of 

as equation (1) 

the age variable is as generally 

(3) IQ * c •• c Aoe • d Pb 

0 1 1 

where c , c , b , b , d = coefficients to be estimated. 

6. The differences between Verbal and performance IQ scores was 

excessive. * We measured the correlation -between verbal and 

performance IQ, and compared the results to those reported by the 

test's designer in his manual. 

7. The means we used to classify subjects' dentine lead levels 

were arbitrary and perhaps biased. The use of ANOVA was not the 

appropriate model to apply. • We took all o£ Ihe. daaiiae. ltad 

le.i_.els for each of the subjects and calculated the arithmentic, 

geometric means, and the median value. Each subject then had a 

single numerical value assigned to his/her lead level. These 

were entered -into a multiple regression analysis as independent 

variables, and the regression coefficients calculated. 

RESULTS AND CONCLUSIONS 

1 & 2. ANACOVA, replacing corrected parent IQ in the model, and 

substitutiong Fathers'education for SES yielded practically the 

same results (Table 1) . In this table, we used 2 variables as 

measures for family size, number of pregnancies and number of 

live births-. We present both variables for information. 

3 & 4. T-tests between included and excluded subjects did not 

show significant differences (Table2>. The dummy variable for 

exclusion had a negative sign, supporting the validity of 

excluding these subjects on the basis of theory, and the 

coeficient for Pb remained positive, and the t value large when 

the excluded subjects were entered into the model (Table 3>. When 

those cases with a history of lead toxiciity were excluded, the 

dummy <oeff i ci en t, -and the coefficient for Pb became increasingly 

negative., supporting the notion of mu 1 t i col 1 i near i ty-.(Jabl e 4>. 
P.17 

5. When age was entered into the model, the coefficients for 

age when the dependent variable was a standardized score became 

negative. The coefficients for Pb when age standardized outcomes 

were used were similar to those obtained when age was enterd into 

regression using raw scores (Table 5) . 

6. The corrrelation between verbal and performance IQ in our 

sample was 6.72, about the same as published by Wechsler in his 

test manual. 7. It should be noted that the 1979 paper did 

control for covariates in the analysis of teachers' ratings. In 

that paper, a sum score of the 11 items was constructed. The 

scores of the high and low lead*subjects were then analyzed by 

ANACOVA, controlling for 5 covariates, and significant 

differences between exposure groups were found after controlling 

4or covariates. 

8. The criticism that stratification of exposures into extremes 

should be examined in the light of the state of knowledge about 

lead at the time that the study was designed(1973). At that 

time, little certainty existed that an effect would be discovered 

at these exposures. The most efficient strategy appeared to be 

to compare the extreme groups, and, if an effect were discovered, 

to look at continuous distributions. Since no lead-free referent 

group existed, we identified individuals acxross the distribution 

of exposures, and then set our referent at the lowest decile. 

Stratification of relatively extreme exposures is the appropriate 

approach to exploratory epidemiology where one is at tempting to 

determine whether an effect exists. This approach maximizes the 

statistical power for a given sample. Extreme non-linearity 

through the middle of a distribution may yield a different 

dose-response relationship for the bulk of the population than 

the linear effect implied. The overall test for the presence:of 

an effect would still be statistically valid. 

In summary, the changes made in this preliminary reanalysis of 

the data(correcting the two parent IQ's, substituting education 

for SES, regressing for age vs raw score, and controlling for 

excluded subjects and missing values), and treating lead level as 

a continuous variable have not materially altered the conclusions 

drawn in 1979. The relationship between lead at low dose and IQ 

appears robust and consistent. 

FINAL NOTE: . The printouts for the material summarrized herein 

are, of course, available for examination in my office in 

Pi ttsburgh. 

Herbert L. Needleman, M.D. 

Department of Psychiatry 

Children's Hosp^taal of Pittsburgh 

- 4 -
P.18 

VARIABLE DEFINITIONS 

AGEINMO Child's age in months. 

PA RENT IQ Parent 10. 

MOMEDUCH Mother's education based on 

Hollingshead scale (with 

value of 1 highest level and 

value of 6 lowest level). 

MOMEDUCG Mother's education—highest grade 

completed. 

DADSOdCL Father's social position based on 

Hollingshead two-factor index 

(the lower the index, the higher 

the social position). 

DADEDUCH Father's education based on Hollingshead scale (with value of 1 

highest level and value of 6 

lowest level). 

DADEDUCG Father's education—highest grade 

completed. 

MOMAGEBR Mother's age in years at child's 

birth. 

NUMPREG Number of pregnancies of mother. 

NUMLIVE Number of live births to mother.-

PBLEV2 Dummy variable for lead level: 

1 if high lead group, 

it otherwise. 

DUMMY DUMMY for excluded case: 

1 if excluded 

I? otherwise 

(Table 2 & 4) 

"RAWVERIQ Verbal IQ - Raw Score 

RAWPERIQ Performance IQ - Raw Score 

FULSCLIQ Full Scale IQ - Standardized for 

A=e 
P.19 

VERBALIQ 

PERIQ 

PBMEAN 

PBMDN 

PBGEMN 

Verbal IQ - Standardized for Age 

Performance IQ - Standardized for 

Age 

Arithmetic mean of tooth dentine 

lead levels. 

Median tooth dentine lead level. 

Geometric mean of tooth dentine 

lead levels. 
P.20 

Main effect: 

Covariates: 

Table 1 

ANACOVA USING VARIOUS TERMS 

Pb Dentin* 

(a) Parent IQ (b) Corrected Parent IQ 

(c) Mother's age at subject's birth (d) Mother's 

education (e) Father's education (f> Father's 

SES (g) Number of live births <h> Number of 

Pregnancies 

MODEL 1 

Covariates: 

FULSCALE 

HIGH 

LOW 

VERBALIQ 

HIGH 

LOU 

PERFIO 

HIGH 

LOW 

X, F p 

(a), (c), (d), (f)f <n> (Original model, 1979) 

102.10 

106.ae 

99. 20 

104.10 

104.90 

108.70 

4.95 

4. 58 

•2. Bl 

0.03 

0.03 

0. 10 

MODEL 2 

Covariates: 

FULSCALE 

HIGH 

LOW 

VERBAL IQ 

HIGH 

LOW 

PERFIO 

HIGH 

LOW 

(b), (c>, (d), (f), <h) 

102.30 4.70 

106.60 

99.30 4.78 

103.90 

104.80 2.34 

108.£0 

0.02 

0. 02 

0. 12 
P.21 

f-DDEL 3 

Covariates: (b), (c), <d>, (f>, <g> 

FULSCALE 

HIGH 101.80 5.92 0.0£ 

LOU 106.90 

VERBALID 

HIGH 99.00 5.40 Z. (&£ 

LOW 104.08 

PERFIQ 

HIGH 104.60 3.40 0.07 

LOW 108.70 

MODEL 4 

Covariates: <b>, (c), (d), (e), (g) 

FULSCALE 

HIGH 102.20. 4.63 0.02 

LOW 106.70 

VERBALIO 

HIGH 99.30 4.30 0.04 

LOW 102.70 

PERFIQ 

HIGH 104.80 2.42 e. 12 

LOW 108.50 

fCDEL 5 

Covariates: (b), (c), (d), (e), (g) 

FJLSCALE 

HIGH 102.20 4.73 0.04 

-OW 106.70 

VZRBALIC 

HIGH 99.20 4.12 0.04 

LOW 102.80 

HIGH 204.90 2.40 0.12 

- LOW 108.50 
Table 2 

T-TEST OF MEANS: MISSING CASES VERSUS 

INCLUDED CASES FOR COVARIATES 

P.22 

RAWVERIQ RAUPERXQ 

MOMEDUCH NA NA 

DADSOCCL** -0.01 -2.80* 

PARENTIQ*** 1.19 0.65 

MOMAGEBR NA NA 

NUMLIVE NA NA 

FULSCLXQ 

NA 

-0.39 

0.9S 

NA 

NA 

VERBALIQ 

NA 

0.99 

1.21 

NA 

NA 

PERIQ 

NA 

-2. 00* 

0.47 

NA 

NA 

NA Too few missing cases to calculate t-statistic. 

* Significant at the .05 level. 

«# N for missing observations is 9; for non-missing, N=147. 

••*N for missing observations is S; for non-missing, N»151. 
P.23 

Table 3 

REGRESSION COEFFICIENTS FDR HIGH AND LOW LEAD SUBJECTS 

WITH TESTS FOR EXCLUSION CRITERIA* 

-

AGEINMO 

PARENTIQ 

MOMEDUCH 

DADSOCCL 

MOMAGEBR 

NUMLIVE 

PBLEV2 

DUMMY 

CONSTANT 

N*** 

R<2) 

SE 

F 

XQVER 

. 6895 

(6.5>* 

.3229 

(5.11)* 

-1.6754 

(1.68)* 

-.6096 

(.60) 

. 1575 

(.97) 

-1.1267 

(1.90)* 

-2.5887 

(1.50)** 

-1.9733 

(.91) 

-22.17 

187 

. 25 

11. 11 

12.56 

IQPER 

.4696 

(2.48)* 

.5551 

.(4.76)• 

-. 9860 

(.55) 

-2.3514 

(1.30)** 

. 1289 

(.45) 

-2.5902 

(2.44)* 

-1.4927 

(.49) 

-7.3107 

(2. 08) • 

17.998 

187 

.22 

19.90 

8.26 

FULSCLIQ 

.4006 

(5.61)* 

-1.4365 

(1.31)** 

-1.1453 

(1.02) 

. 1633 

(.93) 

-1.8372 

(2.85)*.. 

-2.8369 

(1.51)** 

-3.9237 

(1.82)* 

73.7070 

187 

.21 

12. 19 

12. 15 

VERBALIC 

.3612 

(4.94)* 

-1.9652 

(1.75)* 

-. 5652 

(.50) 

. 1662 

(.92) 

-1.3687 

(2.08)* 

-3.2147 

(1.68)* 

-3. £278 

(1.47)** 

72.8218 

187 

T-"7 

m mm I 

12.47 

10.80 

PERIQ 

.2689 

(4.97)* 

-.7072 

(.62) 

-1.4824 

(1.28)** 

. 1646 

(.90) 

-2.0003 

(2.99)* 

-1.7e87 

(.92) 

-3.B61C 

(1.72)* 

77.7332 

187 

.27 

12.68 

10.02 

••• t statistic in parentheses below coefficient 

* significant at tne .05 level, one-tailed test 

••significant at the .10 level, one-tailed test 

•••SAMPLE - All high &r,c low lead subjects tested. 
P.24 

Table 4 

REGRESSION COEFFICIENTS FOR HIGH AND LOW LEAD SUBJECTS 

EXCLUDING 16 CASES WITH LEAD INTOXICATIONS* 

IQVER XQPER FULSCLXQ VERBALXQ PERXQ 

AGEXNMO 

PARENTXQ 

MOMEDUCH 

DADSOCCL 

MOMAGEBR 

NUMLIVE 

PBLEV2 

DUMMY 

CONSTANT 

N*** 

R(2) 

SE 

F 

.8223 

(7.47)* 

.3216 

(4.67>* 

-1.9419 

(1.87)* 

-.3124 

(.30) 

. 1736 

(1.02) 

-1.3294 

(2.16)* 

-3.9813 

(2.16)* 

-3.2964 • 

(1.43)** 

-41.96B7 

171 

.29 

10.92 

14.79 

.6603 

(3.31)* 

.5821 

(4.66)* 

-1.2462 

(.66) 

-1.5315 

(.81) 

.0904 

(.29) 

-3.1972 

(2.89)* 

-4.3341 

(1.20)** 

-11.3078 

(2.71)* 

.0351 

171 

.27 

19.82 

8.96 

.4047 

(5.53)* 

-1.8474 

(1.67)* 

-.5269 

(.48) 

.1060 

(.59) 

- 2. 0246 

(3. 16)* 

-4.9283 

(2.56)* 

-6.8443 

(2.8)* 

75.4569 

171 

.26 

11.62 

14.88 

.3563 

(4.71)* 

-2.3557 

(2. 06>* 

-.1384 

(.12) 

.1128 

(.60) 

-1.4461 

(2.18)* 

-5.0973 

(2.56)* 

-5.8838 

(2.33)* 

76.7141 

171 

.31 

12.00 

11. 85 

.3808 

(4.89)* 

-1.0095 

(.86) 

-. 7900 

(.67) 

. 1163 

(.60) 

-2.£906 

(3.36)* 

-3. 5873 

(1.75)* 

-6.2461 

(2.4)* 

77.8374 

171. 

.29 

10.76 

•«• t statistic in parentheses below coefficient 

V-'mm • 

. * significant at the .05 level, orie-tailed test. 

••significant at the .10 level, one-tailed test. 

•••SAMPLE - All high and low subjects excluding those with 

history of excess" lead or lead poisoning. 
P.25 

Table 5 

REGRESSION COEFFICIENTS FOR 142 SUBJECTS 

INCLUDED IN THE ORIGINAL DATA ANALYSIS* 

AGEINMO 

PARENTIQ 

MOMEDUCH 

• 

DADSOCCL 

* 

MOMAGEBR 

NUMLIVE 

PBLEV2 

CONSTANT 

N*** 

R(2) 

SE 

F 

XQVER 

.8581 

(7.25)* 

.3422 

(4.41)* 

-1.2770 

C1.12) 

-. 2678 

(.24) 

-.0899 

(.49) 

-1.2161 

C.B5>* 

-4.0010 

(1.98)* 

-48.5384 

142 

.29 

10.95 

14. 14 

XQPER 

.7432 

(3.5)* 

. 5600 

(4.1)* 

. .7540 

(.37) 

-2.6233 

(1.3) 

.0331 

(. 10) 

-2.9701 

(2.5)* 

-4.7188 

(1.32)** 

-6.4359 

142 

.23 

19.43 

7.06 

FULSCLXQ 

. 4089 

(4.95)* 

-.7761 

(.64) 

-.7176 

(.59) 

. 0067 

(.03) 

-1.9328 

(2.81)* . 

-5. 1290 

(2.43)* 

73.5861 

142 

.30 

11.66 

11.04 

VERBALIO 

.3808 

(4.46)* 

-1.5138 

(1.21) 

-.0459 

(.03) 

.0114 

(.05) 

-1.3589 

(1.91)* 

-5.0452 

(2.31)* 

72.4527 

142 

.26 

12.02 

9. 19 

PERIQ 

1.2556 

(4.10)* 

. 1602 

(.13) 

i 

-1.2582 

(1.07) 

.0254 

(.12) 

2. 1296 

(2.95>« 

-4.0995 

(l.;85)« 

79.9259 

142 

12.25 

7.77 

* t statistic in parentheses below coefficient 

* significant at the .05 level, one-tailed test 

••significant at the .10 level, one-tailed test 

•«*SAMPLE - All high and low subjects included in analysis 

'• * 
Table 6 

REGRESSION COEFFICIENTS WITH AGE-STANDARDIZED 

DEPENDENT VARIABLE AND AGE INDEPENDENT VARIABLE 

AGEXNMO 

PARENTIQ 

MOMEDUCH 

DADSOCCL 

MDMAGEBR 

NUMLIVE 

PBLEV2 

CONSTANT 

N 

R<2> 

SE 

F 

FULSCLXQ 

-.1661 . 

(1.3)** 

' .4123 

(5.0)* 

-.7607 

(.63) 

-.7986 

(.66) 

-.0213 

(. 11) 

-1.7657 

(2.53)* 

-4.5827 

(2.14)* 

88.1482 

142 

.30 

m. m, . Gtmm 

9.77 

VERBALXQ 

-.1594 

(1.23) 

.3841 

(4.5)* 

-1.4990 

(1.20) 

-.1237 

(.1) 

-.0154 

(.08) 

-1. 1985 

(1.67)** 

-4.5209 

(2.04)* 

86.4275 

142 

.26 

12.01 

8. 12 

PERIQ 

-.1694 

(1.28)** 

.3591 

(4. 14)* 

.1760 

(. 14) ' 

-1.4408 

(1.14) 

.0021 

0 

-1.9591 . 

(2.67)* 

(1.57)** 

94.7888 

142 

. 22 

t Z' Z' Z' 

m 4_> W — 

6. 92 

• significant at the .05 level, one-tailed test, 

••significant at the .10 level, one-tailed test. 
Table 7 

REGRESSION COEFFICIENTS WITH LEAD AS A 

CONTINUOUS VARIABLE* 

AGEXNMO 

PARXQ 

MOMEDUCH 

DADEDUCH . 

MOMAGEBR 

NUMLIVE 

DUMMY 

PBMEAN 

RAWVERIQ 

0.8236 

(8.13)* 

0. 2535 

(4. 12)* 

0.9950 

(1.91)* 

0.1890 

(.52) 

0.1283 

(.81) 

-1.2020 

(2.05)* 

-3.8740 

(1.87)* 

-0.1652 

(2.22)* 

RAWPERIQ 

0.7687 

(4.33)* 

0.5326 

(4.94)* 

-0.2154 

(.24) 

1.7890 

(2.6)* 

-0.1480 

(.53) 

-1.5355 

(1.49) 

-7.8780 

(2. 17)* 

-0.£234 

(1.81)* 

FULSCIQ 

0.3333 

(5.28)* 

0.6312 

(1.18) 

0.7381 

(1.97.)* 

0. 0290 

(. 18) 

-1.4166 

(2.36)* 

-5.6120 

(2.64)* 

-0.1980 

(2.67)* 

SCVERIC 

0.2736 

(4.06)* 

1.0352 

(1.82)* 

0.3792 

(.95) 

0.0677 

(.39) 

-1.2220 

(1.91)* 

-5.5580 

(2.45)* 

-0.2015 

(2.55)* 

SCPERIQ 

0.3366 

(5.6)* 

0. 0667 

(. 12) 

0. 9895 

(2.5);* 

0.0663 

(.04) 

-1.3784 

(2.18)* 

-4.3684 

(1.95)* 

-0.1557 

(1.99)* 

* t statistic in oarentheses oelow coefficient. 

* Significant at the 0.05 level, one tailed test. 

Samslei All subjects excest tr.ose with PI urn Diem and missing 

values. 

*.-••*. 
P.28 

Table 8 

T-TEST OF MEANS: MISSING OBSERVATION CASES VERSUS 

NO MISSING OBSERVATION CASES FOR MEAN, MEDIAN, GEOMETRIC 

MEAN LEAD LEVELS 

T Statistic 

Pb Dentine 

Pb Dentine Pb Dentine Geometric 

Mean Median Mean 

Original Model (N»156) .02 

* 

Entire Sample (N»270) .60 

Low Lead Group (N-133) .86 

High Lead Group (N*85) -.07 

Unclassified Lead Group 

(N=53) -2.09^ -.74 -.43 

. 0 4 

. 9 2 

. 9 7 

-..28 

-.0 3 

1.5 5 

. 8 4 

1. 19 

• Significant at the .05 level.