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THE RELATIONSHIP OF EVENT-RELATED BRAIN POTENTIALS AND LEAD ABSORPTION: 

A REVIEW OF CURRENT1 EVIDENCE* 

(S^^CL^J 

David A. Otto, Ph.D. 

Neurotoxicology Division 

Health Effects Research Laboratory 

Research Triangle Park, NC 27711 

To appear in: L. Vysocki fi: L. Goldwater (eds.) 

Lead Environmental Health: The Current Issues 

^This article has been reviewed by the Health Effects Research Laboratory, 

U.S. Environmental Protection Agency and approved for publication. Approval 

does not signify that the contents necessarily reflect the views and policies 

of the Agency. 

01 
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,1! 

Sensory evoked and slow brain potentials, collectively kriown as 

event-related potentials (ERPs), have been used during the past decade 

to study the effects of lead exposure on central nervous system function 

in hunans and animals. The objectives of this paper are to review these 

studies, to consider the health implications of these data, and to suggest 

future directions for neurobehavioral studies of lead effects in humans. 

ANIMAL STUDIES 

w 

The effects of lead exposure on flash evoked potentials (FEP) in rats 

have been studied by Fox et al (1977, 1979), Feeney et al (19?9) and 

Winneke (1979). Important methodological details and results of these 

studies are summarized in Table I. Although lead-related changes in FEP 

latency or amplitude were observed in each of these studies, the pattern 

of effects was inconsistent across studies. For instance, Fox et al (1977) 

reported increased latencies (conponents Pl, Nl, P2, N2), Feeney et al reported 

decreased (P2) latency, and Winneke found no latency change in Pb-exposed 

animals compared to controls. Winneke, on the other hand, observed depressed 

FEP amplitudes, while Fox et al (1979) observed increased amplitude recovery 

(cortical excitability) to paired flashes in Pb-exposed rats relative to controls. 

A further puzzling inconsistency exists in the reports of Fox et al 

(1977 vs. 1979). The effect of Pb exposure on the recovery function of 

visual cortex was evaluated in both studies — apparently in the 

same animals. Fox et al (1977) reported decreased CNS recovery based on 

latency measures, while Fox et al (1979) reported increased CNS recovery 

(excitability) based on amplitude measures in Pb-exposed animals compared 

to controls. The authors make no effort to reconcile these clearly 

discrepant findings. 
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• 

Inconsistent FEP findings co\ild be due to a variety of methodological 

differences among studies. The Hoses, duration of maternal and offspring 

exposure, age at testing, species or strains of rats, and electrophysiological 

testing methods varied considerably among investigators. Results of these 

studies do suggest, however, that neonatal Pb exposure produced persistent 

effects on visual system function in adult rats. 

HUMAN STUDIES 

During the past eight years a series of collaborative studies by the 

University of North Carolina and the U.S. Environmental Protection Agency 

have been undertaken to explore the effects of asymptomatic.lead exposure 

on neurobehavioral function in children. Three evaluations were made of one 

group of children including an initial assessment in 1978-79 (Otto et al 

19R1), a two-year follow-up in 1980 (Otto et al 1082), and a five-year 

follow-up in 1983 (Otto et al I985, Schroeder et al, I985). A replication 

study in an independent group of children was completed in 1981* (Hawk 

et al 19^5; Robinson et al 1985). The electrophysiological results of 

these studies will be reviewed below. ''. -. 

Two primary sources of exposure were identified in the original 

study group: (l) lead-contaminated dust transmitted into homes on the 

clothing of workers from a battery manufacturing plant; and (2) leadbased paint prevalent in homes built prior to 1950. It should be noted 

that the soil around homes with lead-based exterior paint may be contaminated from weathering even in the absence of peeling paint. The primary 

source of exposure in the replication study was lead-based paint. The 

primary route of exposure in all cases was ingestion. 
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'if I 

I 

higher than in the replication group due to employment in the battery 

plant. Almost all parents of children in the second group were unemployed 

(Hollingshead Class V) . Children ranged in age from 1 to 6 years in the 

initial evaluation, 3 to 7 years at two-year follow-up, 6 to 12 years 

at five-year follow-up, and 3 to 7 in the replication study. See Milar 

et al (1980) and Hawk et al (1985) for additional demographic details. 

Table II summarizes the exposure, medical, psychometric, and demographic measures obtained from children and parents in this series of 

studies. Children with any acute illness, history of perinatal trauma, 

iron deficiency neurological disorder, or frank mental retardation (10 < 60) 

were excluded from data analyses. Socio-economic status, H.O.M.E. scores, 

maternal 10, age and gender were used as covariates or control variables 

in statistical analyses of electrophysiological data. 

Several different electrophysiological tests were used in these studies: 

sensory conditioning (active and passive), pattern-reversal visual evoked 

potential (PREP), and brainstem auditory evoked potential (BAEP). Methodological details of these tests are provided in Otto et al (1985). .The only 

test used in all evaluations was passive sensory conditioning. Active 

sensory conditioning was used only in the five-year follow-up study because 

children under five years of age do not button press reliably. The PREP 

and BAEP were used in the five-year follow-up and replication studies. 

Results of these tests will be reviewed and discussed below. 

Slow wave voltage during sensory conditioning. Electrical activity 

of the brain was recorded from the vertex of children while they watched 

silent cartoons. A warning tone was presented at random intervals 

signalling that the cartoon would be interrupted briefly. This test 
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is a form of classical conditioning in which the warning tone is a 

conditional stimulus (OS) which is paired with a mildly aversive unconditional stimulus (UCS), the cartoon interruption. Electrical activity 

(slow wave voltage) was recorded during the CS-UCS interval and averaged 

across successive trials (1-35 in the initial evaluation; 1-50 and 50-100 

in later evaluations). 

Slow wave voltage during the CS-UCS interval is assumed to be an 

electrophysiological correlate of conditioning — i.e., the child learns 

to anticipate that the cartoon will be interrupted when the warning 

signal is presented. In the passive test, however, there is no behavioral 

measure of conditioning to validate this inference. The functional 

significance of this measure of slow wave voltage, therefore, remains 

uncertain in the passive test. 

Results of sensory conditioning tests in this series of studies are 

summarized in Table III. The initial evaluation (Otto et al, 198l) indicated 

that slow wave voltage varied as a linear function of blood lead (PbB) 

level and that the slope of this function varied with age as shown in 

Figure 1. Results of the two-year follow-up study showed a similar age x 

PbB interaction of slow wave voltage during passive sensory conditioning 

(Otto et al, 1982). Slow wave voltage during passive conditioning, however, 

did not vary with PbB at five-year follow-up. 

Because the children were old enough (6-12 years) to button press reliably 

at five-year follow-up, an active form of the sensory conditioning test was 

added to the electrophysiological battery. Children were asked to press a 

button as quickly as possible when the cartoon was interrupted. The button 

press immediately restored the cartoon enabling children to control the 

duration of the interruption. 
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Figure 2 illustrates waveforms from the active and passive tests. 

Slow wave voltage (negativity) during the CS-UCS interval was much greater 

during active than passive conditioning. The active test thus elicits a 

more robust electrophysiological response than the passive test. Slow 

wave negativity during active conditioning, moreover, increased linearly 

with PbB levels o^ children obtained at five-year follow-un (Otto et al, 

1985). Therefore, the active test also appears to be more sensitive 

than the passive test to the effects of lead exposure in children. 

In the replication study we were constrained to used the passive 

form of the sensory conditioning test because many of the children were 

considered to be too young (three and four years old) to button press 

reliably. No significant relationship of slow wave voltage 'and PbB 

levels were found in this study. We thus failed to replicate previous 

findings (Otto, et al 198l, 1982) in a different group of children. 

Inconsistent findings among the four studies may result from several 

factors. (l) Results of the five-year follow-up study (Otto et al, 1985) 

indicate that the passive test is not particularly sensitive to lead 

exposure in older children. Inconsistent findings may thus be due to the 

relative insensitivity of the passive test. (2) Different types of 

exposures in the two groups of subjects (e.g. secondary occupational_ 

exposure vs Pb-based paint) may produce different neurobehavioral consequences. (3) Methodological differences in data analysis between early 

(Otto et al, 1981, 1982) and later studies may have influenced findings. 

Stricter criteria for accepting single trials in slow wave averages were used 

in earlier studies. More eye movement artifact was tolerated in the fiveyear follow-up and replication studies to increase the number of trials 

in averages for individual children. More trials in averages result in 
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better reduction of noise from unrelated electrical activity of tbe 

brain. ^'^ Previous bindings nay have been Type I statistical errors— 

i.e., slow wave voltage during passive conditioning may not be affected 

by low-to-moderate Pb exposure. Observation of a linear relationship 

of Pb and slow wave negativity during active conditioning (Otto et al, 

19p5), however, argues against this possibility. 

Pattern reversal visual evoked potentials. Tn view of the reported 

effects of neonatal Pb exposure on visual evoked potentials in rats, 

reviewed above, pattern-reversal visual evoked potentials were added to 

the electrophysiological test battery in the fiwi-year follow—up and 

replication studies. Although flash evoked potentials were used in animal 

studies, the pattern-revers-al test was velt'cted for pediatric assessment 

because the PRED has proven to be more sensitive than the FEP in most human 

testing applications (cf. Halliday and McDonald, 1981). 

Pl latency has been found to be the most useful clinical parameter 

of the PREP. Pl latency is delayed in cases of optic neuritis (Halliday et 

al, 1972) and multiple sclerosis (Halliday et al, 1973). We predicted, 

therefore, that Pl latency would vary directly with blood lead levels, but 

this measure did not vary with PbB levels in either the five-year follow-up 

or replication study. Several other PREP measures varied with Pb exposure 

histories of children, however, as shown in figure 3. N1P1 amplitude 

increased (fig 3a) ahd"N2 latency dec'reasecTlfig. "3b) i-n the five-year 

follow-up study (Otto et al, 1985). ' P1N2 amplitude (fig 3c1!) (decreased with 

increasing Pb exposure history in the replication study. 

These findings are problematic for several reasons. (1) Results of 

the two studies are inconsistent — i.e., N1P1 vs. P1N2 amplitudes. (2) 

Results of the five-year follow-up study were contrary to prediction. We 
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hypothesized that undue Pb absorption should produce effects analogous to 

non-specific rtertyelinating disease ~ namely, increased latency and decreased 

amplitude. 'mhe observed relationship 0* ^lNl amplitude and

 pbB in the 

replication study, therefore, was consistent with predictions). (3) From 

a statistical point of view, the -findings are weak, ^he multivariate test 

for the set of PREP measures in both studies was not significant, although 

exploratory univariate tests of certain parameters were significant at the 

.05 level of confidence. 

Shorgia et al (IQ83) and Winneke et al (IQ8I1) have also used PREPs 

in evaluating the effects of Pb exposure in humans. Shorgia et al 

reported increased Pl component latencies in Pb workers compared to 

controls, but Winneke et al found that Pl latency in children decreased 

with increasing PbB within a range of U to 23 ug/dl. The mean PbB 

level of Pb workers in the Sborgia et al study was 62.5 ug/dl. It 

is possible that Pb has a biphasic effect on nerve conduction velocity 

(NCV), facilitating NCV at low concentrations, but slowing NCV at moderate 

to high concentrations. Results of lead studies using PREP measures are 

summarized in Table TV. 

Although we failed to find effects 0^ Pb exposure on Pl latency as 

predicted and as reported by Winneke et al, the pattern-reversal findings 

of the Nordenham study and five-year follow-up study are consistent. PREP 

latencies deceased with increasing PbB levels in both studies. The range 

of PbB levels at the time of PREP testing in the Nordenham (1+-23 ug/dl) 

and five-year follow-up (6-30 ug/dl) studies may be a critical factor. 

The range of current PbB levels in the replication (6-1*7 ug/dl) and 

Shorgia et al (pb-worker mean PbB was 62.5 ug/dl) studies was considerably 

greater. Further research is needed to clarify the inconsistent findings 

concerning the effect of Pb exposure on visual evoked potentials in both 
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humans and animals. 

Hearing and Brainstem auditory evoked potentials. Little evidence 

concerning the effect of Pb absorption on hearing or auditory evoked 

potentials in children is presently available. Auditory processing deficits 

have been reported in cases of Pb poisoning (Jenkins h Mellins, 1957) and 

asymptomatic exposure (Perino & Ernhart, 1°7^; Needleman et al, 1Q7Q). 

Geurit et al (I98l) reported that BAEPs were not affected by Pb exposure 

in children living near a Pb smelter, although the lack of detail in that 

report precludes drawing any conclusions. We therefore conducted a limited 

audiometric screening of hearing threshold (using a 2 KHz pure tone) and 

recorded binaural BAEPs in the five-year follow-up and replication studies. 

Results of these studies are summarized in Table V. 

BAEP results of the five-year follow-up and replication studies are 

shown in figure h. Results of the former study were staight-forward: the 

latencies of BAEP waves III and V increased directly with PbB histories 

of children (fig. kb). Results of the replication study were more complex 

and only partially consistent with earlier findings. Two KHz hearing 

thresholds increased significantly with PbB (fig. ha.) as did I-V interpeak 

latency (an index of central transmission time in the auditory pathway) 

(fig. l*c). Other parameters of the BAEP, however, exhibited a curvilinear 

relationship to Pb exposure history. Latencies of waves III, V and interpeak latency I-III decreased from 6-25 ug/dl, but increased at PbB 

levels above 25 Ug/dl (figure ^c). 

Results of the two studies are consistent for Pb exposure histories 

above 25 ug/dl: BAEP latencies increase directly with the maximal 

PbB values found in the children's medical records. The curvilinear 

functions of BAEP latencies in the replication study suggest, however, 

a possible biphasic effect of Pb exposure on nerve conduction velocity in 
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the auditory pathway with facilitation at PbB levels below 25 ug/dl 

and slowing at PbB levels above 25 ug/dl. 

Perhaps the most intriguing finding from the replication study was 

the significant increase in hearing threshold with increasing Pb exposure 

history. This finding suggests that Pb exposure impairs hearing and the 

peripheral segment of the auditory pathway. This preliminary finding is 

of considerable interest in view of the well-documented association of 

childhood lead poisoning, mental retardation and subtle learning disabilities 

(cf. USEPA, 1977). A selective hearing loss occurring in early childhood 

that remains undetected could result in speech pathology and learning 

impairment as the child grows. Such problems frequently are not identified 

until the child reaches school age and demonstrates performance 

deficiencies. 

Recent confirmation of the effect of lead absorption on bearing thresholds 

has been found in the NHANES II study (Schwartz and Otto, in preparation). 

Andiometric testing of 5000 young people aged h to 19 years old was performed 

with pure tones at 500, 1000, 2000 and 1+000 Hz. Hearing thresholds increased 

significantly with PbB level at the three lowest frequencies tested. 

BAEP findings, moreover, suggest that Pb exposure affects central 

as well as peripheral segments of the auditory pathway. The adjustment 

of click intensity to obtain equal sensation levels in children tested 

in both studies does not permit us to verify the apparent hearing 

threshold effect using wave I latency because wave I latency varies with 

click intensity . In order to evaluate the validity and generality of our 

findings, a comprehensive audiometric, BAEP and speech assessment of an 

independent sample of children at risk for lead poisoning should be undertaken. 
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10 

FUTURE DIRECTIONS IN NEUROBEHAVIORAL LEAD RESEARCH 

1. *

Teed for longitudinal studies. Evaluation of the neurobehavioral effects 

of lead exposure in humans, particularly psychometric data in children, 

has been hampered by the cross-sectional nature of most previous studies. 

Lead exposure history cannot be determined from a single blood lead measure, 

the most widely used metric of lead exposure in cross-sectional studies. 

Tooth lead measures provide an integrated measure of exposure history in 

children, but the limited availability of deciduous teeth and the analytic 

complexity of this measure limit its application. Longitudinal studies 

in which children or workers are sampled at regular intervals to document 

exposure history over an extended period of years offer the best solution. 

The Cincinnati Prospective Lead Project described elsewhere in this volume 

is an excellent example of the kind of longitudinal study needed to clarify 

the significance and persistence of behavioral and electrophysiological 

effects of Pb exposure reported in previous cross-sectional studies. 

2. Need for comprehensive auditory assessment. Results of our recent 

studies (Otto, et al, 1985; Robinson, et al, 1985) suggest that lead exposure affects peripheral and central segments of the auditory pathway. 

Hearing thresholds and central conduction time were both altered in the 

replication study (Robinson, et al, 1985). The implications of subtle 

lead-related hearing loss in young children for subsequent speech and 

learning disorders were noted above. Audiometric evaluations are simple, 

standardized and fairly inexpensive to administer. BAEP testing is also 

fairly simple and standardized, though somewhat more expensive than 

audiometry. We recommend the addition of such tests to future pediatric 

lead studies and to lead worker monitoring programs. 
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11 

Results of BAE*3 testing indicate that this electrophysiological 

measure is very sensitive to the effects o" lead exposure. BAEP testing 

provides valuable information about central conduction in the auditory 

pathway, information that cannot be obtained from audiometric testing. 

Further BAEP studies in lead-exposed children and workers are needed, 

however, to clarify our previous findings. Does lead exposure really 

produce a biphasic dose-dependent effect on auditory function in children? 

Is the effect of lead on auditory function reversible? Are children more 

susceptible to lead-related hearing impairments than adults? Comprehensive 

audiometric, electrophysiological and speech assessments in children and 

adults are needed to resolve these questions. 

3. Need for scotopic vision testing. Studies of visual evoked potentials 

in humans and animals all suggest lead-related alterations, although numerous 

inconsistencies were noted above. Further studies of visual function in 

humans and animals are needed to resolve these inconsistencies. Patternreversal visual evoked potentials, however, may not be a particularly 

sensitive measure to use. A series of in vitro (^ox h Sillman, 1979; Sillman 

et al, 1982; Tessier-Lavigne et al, 1985) and in vivo (Bushnell et al, 1977; 

Fox et al, 19R5) animal studies suggest that rods are more susceptible than 

cones to Pb toxicity. That is, Pb affects night (scotopic) vision more 

than day (photopic) vision in animal models. If lead alters rod, more than 

cone function in humans, then PREPs are unlikely to show any consistent 

effect since the PREP reflects priraarilly cone-mediated vision (Sokol, 

1976). Tests of peripheral and dark-adapted vision in lead-exposed humans 

are needed to resolve this question. 
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h. Need for assessment of cognitive function. An area of considerable 

controversy has heen the *»ffect of l»rM ahsorntion on cognitive 'levelonren^ 

and intelligence in children (c'. contributions of Bornschein, Dietrich, 

Ernhart, Grant, McBride, Smith, Vimpani, Winneke and Yule in this volume). 

Interpretation of cross-sectional pediatric results has been clouded by the 

confounding effects of sociocultural variables. Recent work from our 

laboratory (Hawk et al, 1985) demonstrated an l8-point spead in fullscale Stanford-Binet IQ scores across the

 pb exposure range (6-1*7 ug/dl) 

in three to seven year old children when socioeconomic status was controlled 

in the experimental design. We limited subjects to a subset of the U.S. 

population considered to be at highest risk for lead poisoning—i.e., 

low-income Black children fron SES classes IV and V on the Hollingshead 

Scale. 

A parallel stately of our group has been to use electrophysiological 

indices of sensory conditioning that are considered to be independent of 

standard IQ measures and to be free of the sociocultural biases of IQ tests. 

Early results (Otto et al, 19^1; 1982) suggested that slow wave voltage 

measures obtained during sensory conditioning were sensitive to lead 

exposure in children and were uncorrelated with SES, maternal IQ, child IQ 

or Caldwell H.O.M.E. ratings of care-giving practices. As noted previously, 

slow wave voltage during passive conditioning did not vary with Pb exposure 

history in older children (Otto et al, 1985) or in an independent sample of 

three to seven year old children. 

These inconsistent findings suggest the need for more sensitive and 

reliable electrophysiological measures of cognitive function in children. 

Preliminary results with a modified test indicate that the addition of a 

motor response improves the effectiveness of the sensory conditioning test 

markedlv (Otto et al, 1985). Development of more sophisticated event12 
13 

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related slow potential tests incorporating a P300 paradigm that 

is widely used in cognitive psychophysiology (r.r. Uonchin et a1, 10^8) Recurrently in progress. Oourchesne et al ^1983, 1085) have demonstrated the 

utility of such tests in normal and developmentally disordered children. 

The clinical utility of event-related endogenous potentials has 

been most clearly demonstrated in studies of Alzheimer's disease 

and aging (Squires et al, 1980). "'he latency of the P300 wave, a positive 

ERP that peaks between 300 and 900 msec after presentation of an infrequent or meaningful stimulus, is delayed in patients with Alzheimer's 

disease relative to controls. P300 latency has been associated with 

stimulus evaluation time or "mental chronometry" (Kutas et al, 1977). 

P300 testing can be brief (10 to 20 minutes) and can be administered simply 

in standardized form with commercially available equipment, ""he application 

of P300 methods in neurotoxicity testing has been reviewed recently by 

Harbin (1985). 

Although the effect of lead exposure on cognitive development has 

been studied extensively in children, studies of lead-exposed adults usually 

focus on peripheral nervous system function. Symptoms of acute lead 

poisoning in adults, however, include dullness, irritability, poor • 

attention span, headaches, and loss of memory (reviewed in USEPA, 19.85). 

The syndrome of lead encephalopathy in adults is well-known, but few efforts 

have been made to study the effects of asymptomatic lead exposure on 

cognitive function in adults. In view of increasing evidence that lead 

affects cognitive development in children at lower levels of exposure than 

previously thought (USEPA, 1985), further systematic study of cognitive 

function in lead-exposed adults is clearly needed. Classical neurobehavioral 

testing methods (e.g., Valciukas et al, 1978), computerized behavioral 
test batteries (e.g., Baker et al, 1985) or endogenous ERR methods 

noted above would be appropriate for such studies. 

SUMMARY 

Seiisory evoked and slow brain potentials have been used to study the 

effects of lead absorption on CNS function in both humaiis and animals. 

Results of these studies were reviewed and suggestions for future neurobehavioral lead studies were made. Although the results of individual 

studies suggest that these measures are very sensitive to the effects of 

lead absorption, many inconsistencies among studies were noted, particularlv 

with regard to visual evoked potentials. The pattern-reversal VEP, which 

reflects primarily foveal vision, may be an inappropriate measure of lead 

effects if rods are more vulnerable than cones to exposure. Failure to 

replicate earlier reports of the relationship of slow wave voltage and 

lead exposure suggests that the passive sensory conditioning test is not 

a particularly sensitive measure of lead effects in children. Increased 

auditory brainstem EP latencies with blood lead levels above 25 \ivfil 

were reported in two pediatric studies. Further studies of sensory 

evoked and slow potentials in lead-exposed animals and humans are needed to 

clarify and extend the promising, but limited evidence presently available. 

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14 
ACKNOWLEDGEMENTS 

15 

Support for the Morth Carolina pediatric lead studies was provided 

by NIEHS Grant ES-OHOl*, E^A Contract 68_Q2_1702, and EDA Collaborative 

Agreement CR8099°2 with the University of North Carolina. A large and 

dedicated staff was required to collect and analyze this data. Coprincipal investigator was Stephen Schroeder, Ph.D., University of North 

Carolina School of Medicine. Major contributors included V. Benignus, 

S. Baumann and 0. Robinson (electrophysiology); C. Milar and B. Hawk 

(psychometrics); P. Mushak (analytic chemistry); K. Muller, D. Kleinbanm 

and C. Barton (statistics). The assistance of Lenoir, New Hanover and 

Wake County Health Departments in recruiting subjects, J. Nichols for 

manuscript preparation, and C. Rodriguez for graphics is gratefully 

acknowledged. 
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1^ 

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Mushak, P., Otto, D. (1985). Effects of low-to-moderate lead exposure 

on brainstem auditory evoked potentials in children. Environmental 

Health, Doc. 3 (Neurobehavioral Methods in Occupational and Environmental 

Health), World Health Organization, Copenhagen, pp 177- 1R27 : 
P.20 

18 

25. Sborgia, G., Assennato, 0., L'Abbate, N., DeMarinis, L., Paci, C , 

DeNicolo, M., Demarinis, G., Montrone, N., Ferrannini, E., Specchio, 

L. ,

 Masi, G. fc OiWov-s^ n. 'io.°-5>. !-owr',vi0^sivp <T>oronVvp-:o1r.T-.rn"> 

evaluation o'- .lead-exnosed workers. In: Neurobehavioral Methods 

in Occupational health, 'R. Gilioli, M. , Cassito fc V. Foa, eds.\ 

pp 283-29U,

 percanon Dress, London. 

26. Schroeder, S. , Hawk, B., Otto, D., Mushak, P. fc Hicks, R. (1985). 

Separating the effects of lead and social factors on TO. Environ. 

Res. , 38, (in press). 

27. Schwartz, J. fc Otto, D. (1985I. Blood lead levels, hearing thresholds and 

neurological development in NHANES II children, (in preparation). 

28. Sillman, A., Bolnick, D., Bosetti, J., Haynes, L. fc Walter, A. (1982). 

The effects of lead and of cadmium on the mass photoreceptor potential: 

the dose-response relationship. Neurotoxicology, 3: l79-19l+. 

29. Sokol, S. (1976). Visually evoked potentials: Theory, techniques and 

clinical applications. Surv. Opthalmol., 21: lR—UU. 

30. Squires, K.C., Chippendale, J.S., Wrege, D.S., Goodin, fc Starr, A. 

(1980). Electrophysiological assessment of mental function in aging 

and dementia. In: Aging in the 1980's: Psychological Issues, 

edited by L.W. Poon. Washington, DC: American Psychological Association, 

pp. 125-13U. 

31. Tessier-Lavigne, M., Mobb, P. fc Attwell (1985). Lead and mercury 

toxicity and the rod light response. Invest. Ophthal. Vis. Science, 

26: 1117-1123. 

32. U.S. Environmental Protection Agency (1985). Air Quality Criteria for 

Lead, Vol. IV, FPA-600/8-83-028A (in press). 

33. Valciukas, J., Lilis, R., Eisinger, J., Blumberg, W., Fishbein, A. fc 

Selikoff, I. (1978). Behavioral indicators of lead neurotoxicity: 

Results of a clinical field study. Int. Arch. Occup. Environ. Health, 

1+1: 217-236. 

3U. Winneke, G. (1979). Modification of visual evoked potentials in rats 

after long term blood lead elevation. Activ. Nerv, Sup. ^praha), 

21: 282-281+. 

35. Winneke, G., Beginn, TI., Ewert, T., Havestadt, C , Kramer, U., 

Krouse, Ch., Thron, H. fc Wagner, H. (198I+). Studie zur Erfassung 

subklinischer Bleiwirkungen auf das Nervensystem von Kindern mit 

vekannter pranataler Exposition in Nordenham. Schr.-Reine Verein 

Wabolu, 59: 215-229. 
TABLE I. EFFECTS OF NEONATAL LEAD EXPOSURE ON FLASH EVOKED POTENTIALS (w.p) TN RA^P 

;TUDY 

SPECIES/NUMBER 

OF ANIMALS EXPOSURE INFORMATION 

SIGNIFICANT 

RESULTS 

"ox et al, 1977 Long-Evans 

(6 animals/treatment/ 

age) 

Newborn rats exposed to Pb 

via dam's milk; drinking 

water of dams contained 0.2*' 

Pb acetate. Exposure ceased 

at weaning (21 days). 

Mean blood/brain Pb levels: 

Controls Exposed 

dy 21 6/7 65/53 Pg/dl 

dy 90 5/11 7/13 

1. FEP latencies (Pl ,

wl ,P? ,*>2) were 

longer in Pb-exposed rat^ during 

development (days 9-1?, 16, 20) 

and as adults (day °0). 

2. Development of EEP components was 

delayed in Pb-exposed nts. 

3. Latency recovery to pai red flashes 

was decreased in Pb-exr'^ned rats 

at 90 days. 

1*. Frenuency-following response to 

repetitive "lashes was •iecreaser' 

in Pb-exposed adult rats. 

ox et al, 1979 Long-Evans 

6 controls 

6 exposed 

?eney et al, 1979 CD rats 

9 controls 

8 exposed 

Same day-O0 rats as above 

Newborn rats exposed to Pb 

via dam's milk, potential 

dams received 750 mg/kg Pb 

acetate dissolved in drinking water from day 21 until 

weaning of pups. No blood 

or Pb data provided for 

animals tested. PhR levels 

from duplicate sample exposed dams were 117 ug/dl 

at weaning vs. '> ug/dl for 

control dams. Estimated PbB 

levels of all animals at testing-was—<lt ug/dl. 

Rats exposed neonatally to Pb showed 

increased cortical excitability (P2/ 

Rl amplitude ratio of resoonses to 

paired flashes) compared to controls 

FEP latency (P2 only^ in ~*n_Ro dayold rats was shorter in

 P^-exposed 

than control animals. 
•UDY 

SPECIES/WTIMRER 

OF ANIMALS EXPOSURE INFORMATION RESULT. 

inneke (1979) Wistar 

10 animals/ 

treatment 

For 60 days prior to mating: 

dams fed 1* diets: control, 750, 

2260, or 67)i0 ppm Pb-acetate. 

Observed

 pbR levels in dams 

were: <5, 2U, 53 and 87 ug/dl. 

PbR levels in offspring after 

110-190 d of postnatal Pbfeeding: <5, 29, '*0, and 6b 

Ug/dl. 

Pats were tested at 150-190 dayr 

of age. ^EP amplitudes 'N1,N1P^) 

were lower in two high'--.t exposure 

groups than controls, "hreshold 

effect level of 30-H0 i^'d 

noted. No Pb-related ^-lhency 

effects found. 

ro 
P.23 

TABLE II. SUMMARY OF EVALUATIONS 

I. Exposure Evaluation 

A. Fantus Lead

 Doisoning Ouestionnaire 

B. Rlood Lead 'Ph*>^: ^laneless Atomic Absorption Spectrometry 

C. Free Erythrocyte Protoporphyrin (FEP) 

II. Medical Evaluation 

A.

 Medical History 

B. Pediatric Neurological Examination 

C. Growth: Height, Weight, Head Circumference 

D. Lab Tests: BDS, WBC, RBC, Hgb, HCT, MCV, MCH, MCHC 

III. Electrophysiological Evaluation 

A. Slow Cortical Potentials during Sensory Conditioning 

B. Brainstem Auditory Evoked Potentials 

C. Pattern-Reversal

 visual Evoked Potentials 

IV. Psychometric-Behavioral Evaluation 

A. Stanford-Binet Intelligence ^est-Revised (Children over 30 months) 

B. Bayley Scales of Mental Development (Children under 30 months) 

V. Demographic Covariate Evaluation 

A. Maternal IQ: Amraons Quick Test pr Peabody Picture Vocabulary Test 

Revised 

B. Socioeconomic Status: Hollingshead ''Vo-Factor Index 

C. Quality of Caregiving Environment: Caldwe.ll's Home Observation 

for Measurement of the Environment 

D. Chronological Age 

E. Sex 
TARLE III. RELATIONSHIP OF SLOW WAVE VOLTAGE AND PbR LEVELS DURING SENSORY CONDITIONING 

STUDY 

NUMBER OE 

SUBJECTS IN 

DATA ANALYSIS 

AGE 

(YEARS) 

PbR AT 

TESTING 

(ug/dl) 

TYPE OF 

CONDITIONING PPTULT'-

NITIAL EVALUATION 

Otto et al, 1981) 

-YEAR FOLLOW-UP 

Otto et al, 1982) 

»»1 

28 

1-6 6-55 

3-1 ll»-39 

PASSIVE SLO" WAV? "Of/PAGE '.''"TED ! 

(35 trials ) AS A LINEAR EUNCT.ir— OF I 

PbB AND AGE I 

PASSIVE 

(100 trials) 

I 

SLOW WAVE VOLTAGE v -.^IED ! 

AS A LINEAR PirMPTTO" OF ! 

PbR AND AGE DURING ' ^TR 

TRTAI.S (hl-lOO) ONT,--' 

-YEAR FOLLOW-UP 

Itto et al, 1985) 

I18 6-12 6-30 PASSIVE 

(100 trials) 

AND 

ACTIVE 

(50 trials) 

AS A LI "EAR FUMC'riP'1' OF 

CURRENT PhB DURING 

ACTIVE, Rtrn NOT DUR •"•''I 

PASSIVE CONDITIONING 

^PLICATION STUDY 

)tto et al, in 

-(reparation) 

68 3-7 6_>i7 PASSIVE 

(100 trials ) 

SLOW WAVE VOr,,T,AOE D n NOT 

VARY WT,n>T PbR LEVEL" OR 

AGE 

to 

J* 
TABLE IV. RELATIONSHIP OF PATTERN-REVERSAL VISUAL EVOKED PO^EN^IAL MEASURES AND PbR 

STUDY 

NUMBER OF 

STTBJECTS IN 

DATA ANALYSIS 

AGE 

(YEARS) 

PbB AT 

TESTING 

(ug/dl) RESULTS 

i et al (1983) 31 Exposed 

37 Control 

142 62.5 

19.0 

REPORTED INCREASED Pl LATENCIES IN Pb-WOR1'

,-c?S 

COMPARED TO CONTROLS 

e t a l (1985) 122 6-7 H-23 REPORTED DECREASING ^1 LATENCY WI^u I'IPRE ; TNG 

PbR 

Follow-ti p 

?t. al , 1985) 1*3 6-12 6-30 N1P1 AMPLITUDE INCREASED AND Np LATENCY 

DECREASED WITH INCREASING ORIGINAL PbR 

ition Study 70 3-7 6-H7 P1N2 AMPLITUDE DECREASED "TTH INCREASING ^'.R 

(MAXIMAL = 6-56 ug/dl) 

:y> 
TABLE v. RELATIONSHIP OF BRAINSTEM AUDITORY EVOKED POTENTIAL MEASURES AND PbR TN CHILDRE" 

STUDY 

NUMBER OF 

S'TRJECTS IN 

DATA ANALYSIS 

AGE 

(YEARS) 

Pb (ug/dl) 

a. CURRENT 

b. MAXIMAL RESULTS 

-YEAR 

OLLOW-UP 

">tto et al, 1985) 

1*5 6-12 a. 

b. 

6-^0 

6-50 

'^PLICATION STUDY 

">tto et al, in 

oreparation) 

65 3-7 a. 6-^7 

b. 6-S6 

1 

t 

WAVE III AND V LATENCIES TNCP1'

 -'"ED ! 

LINEARLY WITH INCREASING M-'VXP".',, I 

BUT NOT CURRENT PbR I 

(1) HEARING THPESHOLD INOREAS'-'' 

LTNEARLY WITH PbR (OMRREN"' AND 

MAXIMAL). 

(2) WAVE I LATENCY DECREASED 

LINEARLY WI^H PbR (CURREN'" AND 

MAXIMAL). 

(3) WAVE TTT, V LATENCIES AND TPL 

I-IIT, T-,r SHOWED OURVU.r'^AR 

RELATIONSHIP TO PhP (MAXT"AL 

ONT.Y). 

(ll) TPL I_V INCREASED LT*'EARL-7 WITH 

PbR (MAXIMAL ONLY) 

r 

r.4 
P.27 

?5 

FIGURE LEGENDS 

"J,r.i-->i 1. "r.'.e:•:;-.• M •••: c"'e;:!,s o'~ a^s an*) blood lfif.il ievr-;Is on :;.'.ov 

wave voltage in children during passive sensory conditioning. 

Predicted slow wave voltaee and OS1*, confidence limits are 

depicted as a function of original blood lead levels at the 

extreme ages of subjects at initial evaluation. (.Adapted 

from Electroenceph. Clin. Neurophysiol., IQ81, S2: 235^. 

Figure 2. Summary averages or slow potentials observed at

 rrontal 

(•^z), central (Cz^ and parietal recording sites in children 

during active and passive sensory conditioning (five-year 

follow-up evaluation^. The electro-oculogram (FOG) recorded 

from electrodes above and below the right eye is also shown. 

Horizontal bars above averages depict intervals during which 

conditioned (CS) and unconditioned (UCS) stimuli were presented. 

Slow wave measurement intervals (SWI and SW2) are designated 

by vertical lines. Note that slow wave voltage is much 

greater during active than passive conditioning. 

Figure 3. Scatter plots and regression lines for N1P1 amplitude (a), 

N2 latency (b) and P1N2 amplitude (c) of the pattern reversal 

visual evoked potential as a function of maximal blood lead 

levels of children. (a) and (b) were obtained from chidren 

aged 6 to 12 years in the five-year follow-up study. (c) was 

obtained from children aged 3 to 7 years in the replication 

study. 

Figure 1*. Scatter plots, regression lines, and 95*> confidence limits of 

(a) hearing threshold, (b) BAEP wave V latencies of boys and 

girls in the five-year follow-up study, and (c) BAEP wave V 

and interpeak V-I latencies of children in the replication study 

as functions of maximal blood lead levels. Hearing thresholds 

were determined audiometrically using a 2 KHz pure tone in the 

replication study. A linear relationship of wave

 v latency^and 

PbB was found in children aged 6 to 12 years (b), while a curvilinear 

relationship was found in children aged 3 to

 7 years (c^. 
• yr-mfrrfTwirj 

30-

20i— 

w ° -

5 10 15 20 25 

^ J^'''''ir':'

:

'

:

li*::?s>.>. 

^^HMONTHSij|;S::S:*S; 

30 3b 40 .45 50 55 60 

fb. fj|/dl 

V 

ACTIVE 

UCS. CARTOON OFF 

EOG 

SOO 1000 

TIME, miec 

1500 

«i 
P.29 

40 — 

C 30 

20 — 

10 

a. 

• 

i 

F = 7.22 

c!1 1 tO 

p; .01 

• 

• 

• 

• 

• 

• 

1 

t 

• • 

• • 

| 

• 

• 

• 

• 

• • • 

i 

• 

• 

| 

• 

• 

• 

• • 

I 

• • 

• 

| 

• 

• 

1 

• 

t00"9^ 

I 

\ 

• 

"^ 

~~ 

^ 

• 

10 20 30 40 

ORIGINAL BLOOD LEAD.^g/dl 

50 60 

200 — 

180 — 

u 

2 160 

140 

120 — 

100 

b. 

• 

— 

1 

• 

• •• 

• • • 

1 

• 

• 

• 

1 

• 

• 

• 

• • 

• • 

1 

• 

• 

• 

• 

• 

• 

• 

o 

1 

• 

— • 

!• 

1 

• • 

• 

• 

• 

1 

• 

• 

• 

• i 

F = 5.56 

df=1.4 1 , 

p=..022 • 

• 

• 

• 

•I 

• 

10 20 30 40 

ORIGINAL BLOOD LEAD, jsg'dl 

50 60 

30 

25 — 

20 

O 

3 

r

1

 15 

2 10 

;C. F|1.68) = 11.57 

p = 0.001 

r

2

 = 0.15 

10 20 30 40 50 

MAXIMUM PbB CONCENTRATION./;g/dl 

60 

W 
WAVE V LATENCY, msec HEARING THRESHOLD, dB SPL 

"TT 

oed