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Journal of Occupational & Environmental Medicine:
Original Articles

Brainstem Neural Conduction Biomarkers in Lead-Exposed Children of Andean Lead-Glaze Workers

Counter, S. Allen DMSc, PhD

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Author Information

From the Department of Neurology, Harvard Medical School; The Biological Laboratories, Harvard University, Cambridge, Massachusetts.

Address correspondence to: Dr S. Allen Counter, Neurology/Harvard Medical School, The Biological Laboratories, 16 Divinity Ave, Cambridge, MA 02138; e-mail allen–Counter@harvard.edu

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Abstract

Pediatric lead (Pb) intoxication remains a major medical challenge in some developing countries where Pb is used in glazing industries. Pb exposure is reported to induce neurophysiological and neurocognitive impairment in children. However, the threshold and level of Pb intoxication necessary to induce neuropathology have not been established. Brainstem auditory evoked responses (BAERs) have been used widely as a sensitive biomarker for Pb-induced neurotoxicity. In this field study, BAER neural conduction time was used as a biomarker for central nervous system impairment in Andean children living in areas of high Pb contamination from Pb-glazing cottage industries. The mean Pb level in blood (PbB) for 112 Pb-exposed children was 49.25 μg/dL (SD, 27.0 μg/dL; range, 4.4–119.1 μg/dL). Although BAERs in some children showed prolongations in neural conduction times, regression analyses revealed no significant correlation between PbB levels and BAER interpeak conduction times for 112 replicate recordings (I–III, r = 0.008, P = 0.93; III–V, r = 0.13, P = 0.16; I–V, r = 0.09, P = 0.35; and I–VI, r = 0.14, P = 0.27). A subgroup of 69 children in the study area with PbB levels in the United States Centers for Disease Control and Prevention (CDC) medical intervention-emergency classifications (CDC IV and V; mean, 67.0 μg/dL; SD, 15.8 μg/dL; range, 45.1–119.1 μg/dL) showed no significant correlation between PbB and BAER interpeak interval and no significant differences in BAER than a normal subgroup (t test, P > 0.05). The results demonstrate some evidence of abnormal, possibly Pb-induced neural conduction delays in some individual children but a remarkable overall neurobiological functioning in severe, chronic pediatric Pb intoxication without measurable impairment of brainstem auditory nuclei and tracts, as evidenced by neurophysiological conduction times. The findings also demonstrate the variability in the threshold level and duration of Pb exposure necessary to induce brainstem neuropathology.

Pediatric lead (Pb) poisoning remains a prevalent medical challenge in impoverished communities of the United States and in many developing nations where Pb is widely used in petroleum, paint, ceramic glazing, and Pb-acid battery industries. 1–3 The diverse neurotoxic effects of Pb exposure in children, including severe sensory, motor, and cognitive neurological impairment, have been widely reported in the medical literature. 4–10 Nevertheless, the Pb body burden and the duration of Pb intoxication that must exist before pediatric neurodevelopmental disabilities are evident have not been firmly established. The threshold and tolerance levels for Pb neurotoxicity and consequent Pb-induced pediatric neurological impairment appear to be variable. Some children present with neurological and behavioral signs of Pb poisoning at low Pb exposure levels, whereas others appear to have a higher threshold for Pb-induced neurotoxicity. 11–16 Individual genetic susceptibility to Pb intoxication has also been suggested as a contributing factor in pediatric plumbism. Recent scientific evidence suggests a genetic polymorphism in susceptibility to Pb intoxication in some human populations. 17–19 This inference may have some bearing on the disparate findings in the neurological outcomes of Pb intoxication reported for some populations. However, the prevailing tenet in environmental neuroscience is that pediatric plumbism induces irreversible neuronal lesions from the brainstem to the cerebral cortex, even at low levels of Pb exposure. 20

The most widely used biomarker for clinical Pb intoxication is whole-blood Pb concentration. The health-based biological limits for a range of blood Pb (PbB) levels have been established by the United States Centers for Disease Control and Prevention (CDC). 21 A second biomarker that has been used in neurobiological studies to detect Pb neurotoxicity in humans and experimental animals is the brainstem auditory evoked response (BAER). 22–24 This noninvasive, scalp-recorded electrophysiological response to auditory stimulation measures volume conducted potentials from axonal and transsynaptic activity in the neurons of the ascending auditory tracts from the eighth nerve to the pons and midbrain. Several clinical studies have reported that BAER waves serve as a sensitive detector of Pb-induced neurotoxicity. 25–27 The sensitivity of the BAER recording technique as well as the portability of equipment for measuring BAERs make it a suitable bioassessment tool for field investigations of neurotoxicity in Pb-exposed children, particularly in remote and isolated areas without conventional clinics and inaccessible to modern medical care.

Exceptional pediatric plumbism has been observed in a population of children living in a highly Pb-contaminated enclave where occupational Pb glazing of ceramics is the primary cottage industry. 28 Initial observations of neurosensory function in a small group of the children in this Pb-exposed population showed no evidence of Pb-induced neuroauditory impairment. 28,29 The absence of measurable brainstem neurological damage in these Pb-intoxicated children raised questions regarding the threshold of Pb neurotoxicity in different populations, polymorphisms or genetic predispositions to Pb-induced impairment, and individual susceptibility, as well as the validity of previous reports of brainstem impairment at low to moderate Pb exposure levels. The objective of this study was to investigate the threshold and neurobiological effects of Pb intoxication in a large group of children with chronic (lifelong) and high environmental Pb exposure by using field measurements of BAER neurophysiological activity as a biomarker.

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Materials and Methods

Location

This study was conducted in the field, in the Andes Mountains of Ecuador, South America, among indigenous people who have little access to medical care. The participants in this study live in unique enclaves of extremely high Pb contamination. Studies among members of these communities during the course of medical care may provide the medical and scientific community with a better understanding of the impact of long-term and chronic Pb exposure. The first study area is located in the village of La Victoria, approximately 125 km south of Quito, Ecuador, at an altitude of about 2850 m above sea level. The second study area is located in the village of Racar, located approximately 15 km west of the southern Ecuadorian city of Cuenca, at an altitude of 2500 m. The primary source of Pb exposure for children in both study area villages is that of discarded Pb-acid automobile storage batteries, from which the Pb is extracted manually by adults and children and churned into a slurry for use in the glazing of commercial ceramic roof tiles and artisan crafts. The liquid Pb glaze is baked onto the ceramics in large kilns fueled mainly by tree branches and sawdust, with the Pb-laden smoke from the many village kilns saturating the study area.

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Participants

BAER tests were conducted by a neurophysiologist on 112 children aged 2 to 15 years (mean age, 9.0 years) over a period of several years as part of an ongoing series of studies. The weight of the children ranged from 10 to 56 kg (mean, 21.2 kg). The height ranged from 94 to 148 cm (mean, 111.8 cm). The children were brought to the field clinic testing site by their parents, local schoolteachers, and the principal. The children have a lifelong history of chronic plumbism, which is believed to have begun prenatally and continued throughout childhood from the ingestion of Pb-contaminated food. All children tested were selected on a random basis from several classrooms at the local school located in the study area, and each child lived and played in the Pb-contaminated study area. The children were given medical examinations by medical doctors and audiological evaluations by a certified audiologist before the BAER measurements. Physical examinations at the time of medical testing showed that three children had peripheral neuropathies in hands and feet, four showed gait disorders, six exhibited attention deficit disorders (with hyperactivity), three children complained of balance disturbances, one presented with microcephaly, and 12 children showed evidence of neurocognitive impairment on examination. No evidence of severe visual or hearing impairment or gross motor dysfunction was observed. A summary of the children’s medical complaints as reported by the children themselves or by their parents indicated that 27% had frequent constipation, 38% reported frequent diarrhea, 37% reported colic, 28% reported vomiting, 46% reported frequent headaches, 25% reported stomach cramps, and 41% reported irritability. Because no effort was made to select specific children and because the children were selected from several grades, the sample of village children tested in this study is believed to be representative of the population of children in the study areas. Informed consent was obtained from the parents or guardian of the children before testing. This study was approved by the Human Studies Committee of Universidad San Francisco de Quito Medical School. The study was conducted under the auspices of the Universidad San Francisco de Quito Medical School in Quito, Ecuador.

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Blood Tests

Blood samples were collected at the testing site before the BAER test was administered, and no knowledge of the participants’ PbB level existed at the time of the neurophysiological tests. Venous blood samples of 2 to 4 mL were drawn from each of the children with standard Vacutainer (Becton Dickinson, Rutherford, NJ) blood collection sets with Li-heparin after repeated skin cleansing with water or soap and water and isopropanol swabs. The whole-blood samples were stored in the field in a refrigerated container at approximately 4°C and analyzed approximately 1 week later for Pb concentrations by inductively coupled plasma mass spectrometry (ICP-MS; Sciex Elan 5000, Perkin-Elmer, Norwalk, CT) at the Channing Laboratory of the Harvard School of Public Health. The ICP-MS analysis was conducted with standard instrument operations and data collection parameters with isotope-dilution procedures. Four empty tubes from the same batch used at the field test site were later tested in the laboratory for metal contamination and found to be Pb-free. For purposes of establishing reference levels and clinical utility, the PbB levels were grouped according to the classifications of the CDC 21 on PbB in children: classes I (<10 μg/dL: not considered Pb poisoned), IIA (10–14.9 μg/dL: abnormally elevated PbB level; frequent rescreening and community Pb-prevention activities recommended), IIB (15–19.9 μg/dL: abnormally elevated PbB level; nutritional, educational, and environmental interventions and frequent screening recommended), III (20–44.9 μg/dL: environmental evaluation and remediation and medical evaluation recommended; pharmacological treatment may be indicated), IV (45–69.9 μg/dL: environmental and medical interventions, including chelation therapy recommended), and V (≥70 μg/dL: medical emergency; immediate medical and environmental management recommended).

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Brainstem Auditory Evoked Responses

BAERs serve as a field-portable, objective method of assessing the neurological integrity of the eighth cranial nerve, pons, and midbrain. 30 Electrophysiological BAER measures of neural conduction capacity have been used routinely as an assessment tool for evaluating the integrity of the ascending brainstem auditory tracts and nuclei in neurological diseases. 31 All BAER examinations in the present study were conducted by the neurophysiologist in the field with the instrumentation being transported to the test site in the Andes Mountains by vehicle or on foot when vehicular transportation could not be used. Each participant was screened for hearing loss by audiological tests, and sensorineural hearing loss was ruled out before BAER testing. Electricity was provided by local generators, portable generators, or the battery of an automobile with a running engine. The BAER tests were performed in a quiet ambience with the patient placed in a reclining position. In preparation for the electrophysiological tests, the scalp, forehead, and ear lobes were thoroughly cleaned with water and swabs containing isopropanol, and gold-plated electrodes were placed at Cz, A1, A2, and Fpz (according to the 10-20 International Electrode System). The electrodes (vertex-positive) were connected to a standard preamp (105), with filter settings at 100 to 3000 Hz, in a Medlec/GSI 50 computer averager. Broad-band monaural, rarefaction click stimuli of 100-μsecond duration were delivered to the ear/side under test through TDH 39 headphones at a rate of 10 pulses per second (pps), averaging 1024 to 2048 sweeps per trial with contralateral masking. The intensity level of the click stimulus was increased when BAER responses were unclear at 70 dB normal hearing level (nHL) with no effect on the interpeak latency but was taken into consideration in absolute latency measurements (70–80 dB HL was found to be a useful BAER threshold level for field testing). Additional BAER recordings were made at a stimulus repetition rate of 50 click pps for confirmation of peak amplitude and latency measurements in relation to clinical norms. Recordings of wave VI were made for additional information regarding the functional integrity of the higher auditory tracts and nuclei in the midbrain. 32 All BAER measures were repeated immediately, and the on-line recordings were superimposed for reliability testing. The BAER traces were printed on paper, with the y axis measured in nanovolts (nV) and the x axis measured in milliseconds (ms). The average time for a complete BAER test on each patient in the field, from preparation of the scalp for electrode placement to post-test electrode removal and cleaning, was approximately 60 minutes. Noninvasive BAER measures of neurological function were preferable and widely accepted by the parents of the Andean children tested. Sample neurophysiological BAER recordings acquired in a United States clinic from a normal 7-year-old girl with no history of Pb exposure, using the same GSI/Medlec test equipment that was used in this field study, are shown in Fig. 1.

Fig. 1
Fig. 1
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Statistical Analysis

Data from BAER recordings were analyzed bilaterally, in some cases with only one side (left ear) used for the analysis of results when there were no significant intra-aural differences in the mean absolute and interpeak latencies. The mean and variability of the absolute and interwave peak BAER latencies were analyzed statistically. Regression analyses were used to analyze the relationships between PbB level and the neurophysiological interpeak conduction/transmission times. The t test was used to determine statistical significance between mean neural conduction times for children in the CDC IV, V, and I classifications. A confidence level of ≤0.05 was accepted as an indication of statistical significance.

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Results

PbB Level

ICP-MS analysis indicated that the mean PbB level for the 112 children in the study areas who received BAER tests was 49.25 μg/dL (SD, 27.0 μg/dL; range, 4.4–119.1 μg/dL). The subjects were subdivided into the most severe Pb-intoxicated CDC classifications for closer analysis (IV and V). The mean PbB level for the 45 children in the CDC IV classification was 58.0 μg/dL (SD, 7.3 μg/dL; range, 45.1–69.5 μg/dL), while the mean PbB level for 24 children in the CDC V classifications was 84.0 μg/dL (SD, 13.2 μg/dL; range, 70.5–119.1 μg/dL). The mean PbB level for the combined 69 children in CDC IV and CDC V classifications was 67.0 μg/dL (SD, 15.8 μg/dL; range, 45.1–119.1 μg/dL).

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Brainstem Auditory-Evoked Responses

The mean BAER absolute wave peak latencies and interpeak intervals of waves I through VI for the 112 children were within the normal range (Table 1). A regression analysis of 112 replicate, unilateral BAER recordings (shown in Fig. 2) indicated that the quantitative relationship between PbB level and interpeak intervals did not reach statistical significance for interpeak intervals I through III (r = 0.008, P = 0.93), III through V (r = 0.13, P = 0.16), and I through V (r = 0.09, P = 0.35).

Table 1
Table 1
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Fig. 2
Fig. 2
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Separation of the 69 children with the highest PbB levels (CDC IV and V classifications; range, 45–119 μg/dL) revealed no significant correlation between the PbB level and bilateral neural conduction times in the interpeak latencies (for 138 replicate recordings). Regression analyses for the relationship between PbB levels and interpeak latency intervals for the bilateral (left and right) BAERs of children with PbB levels in the CDC IV and V classifications did not show statistical significance: left BAER intervals I through III (r = 0.09, P = 0.47), III through V (r = 0.17, P = 0.16), and the I through V (r = 0.06, P = 0.65); right BAER intervals I through III (r = 0.04, P = 0.72), III through V (r = 0.22, P = 0.07), and I through V (r = 0.22, P = 0.07).

The mean absolute and interpeak interval latencies for wave VI measured in 64 children in the study group with PbB levels in the CDC I through V classifications, for whom wave VI could be clearly identified, was found to be within the normal range (means for wave VI, 7.0 ms; I–VI, 5.4 ms; III–VI, 3.3 ms; and V and VI, 1.5 ms). A regression analysis (shown in Fig. 3) indicated that the relationship between PbB level and the absolute and interpeak latencies referenced to wave VI did not reach statistical significance: wave VI (r = 0.22, P = 0.08), I through VI (r = 0.14, P = 0.27), III through VI (r = 0.17, P = 0.17), and V to VI (r = 0.16, P = 0.22).

Fig. 3
Fig. 3
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The mean BAER interpeak latencies of waves I through VI for 11 healthy children from the study areas with similar backgrounds, ages, weights, and head sizes and with PbB levels in the CDC I classification (mean PbB level, 7.45 μg/dL; range, 4.4–9.9 μg/dL) are also shown in Table 1. A t test showed no statistical significance between means for interpeak intervals in 69 unilateral BAERs of children with the CDC IV and V PbB levels and the 11 BAERs in the healthy children (I–III, t = −0.184, P = 0.854; III–V, t = −0.053, P = 0.957; I–V, t = −0.119, P = 0.905; VI, t = −01.88, P = 0.064).

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Case Profiles

The following cases are presented to illustrate the relations between PbB levels and BAER responses in some of the highly Pb-intoxicated children with PbB levels in the upper CDC V classifications (≥70 μg/dL).

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Case 1.

This is a 10-year-old boy with a PbB level in the CDC V category (118 μg/dL) who received PbB and BAER tests over a 2-year period and whose parents were Pb-glazing workers. The child was found to have microcephaly and was reported by the parents and teachers to be developmentally delayed, with a family history of mental retardation. He exhibited dental Pb lines and deficits with fine motor sequencing, graphomotor skills, and math proficiency. The patient was recommended to the Ecuadorian medical authorities for pharmacological intervention. Chelation therapy was provided for the child for the first time in 1999 with the succimer 2,3-dimercaptosuccinic acid (DMSA) by a biomedical team that included a local doctor. The treatment outcomes will be reported in a separate study. Figure 4 shows the patient’s replicate left BAER recordings. The V-I ratio is low and may reflect pontine-level damage.

Fig. 4
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Case 2.

This is a 6-year-old girl with a PbB level in the CDC V classification (mean, 100.2 μg/dL; range over a 3-year period, 95–128 μg/dL) who received PbB and BAER tests over a 3-year period. The child was observed to assist her parents in the Pb-glazing process. She was found to have normal sensory and motor function, with no sign of neurological or other medical abnormalities on physical examination. Language skills were normal and age-appropriate. Otoscopic examination revealed dark-colored (presumably from exposure to Pb-laden smoke and dust) impacted wax mainly in the left ear. The patient was recommended to the Ecuadorian medical authorities for otological treatment and pharmacological intervention. Chelation therapy was provided for the child for the first time in 1997 by the Ecuadorian health authorities with dimercaprol, or British anti-lewisite, and again in 1999 with DMSA by a biomedical team that included a local doctor. The treatment outcomes will be reported in a separate study. Figure 5 shows the patient’s replicate BAER premedication tracings. The BAER revealed normal absolute and interwave latencies at 80 dB HL. The BAER recordings in the left ear at 70 dB HL suggest a mild conductive hearing loss. A 10-dB increase in click stimulus intensity to 80 dB HL evoked waves I through VI with normal temporal and morphological features.

Fig. 5
Fig. 5
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Case 3.

This is an 11-year-old boy with a PbB level in the CDC V category (119.1 μg/dL) who received PbB and BAER tests over a 3-year period. He had a history of assisting his parents in Pb-glazing activities since the age of 6 years. The child was found to be physically and mentally normal, with no sign of neurological impairment. His language skills and sensory motor function were age-appropriate. Figure 6 illustrates the patient’s bilateral BAER recording at 70 and 80 dB HL, made at the time of the blood sample collection. The absolute and interwave latencies and amplitudes of wave peaks I through VI were within the normal range bilaterally at both 10 and 50 pps. The patient was recommended to the Ecuadorian medical authorities for pharmacological intervention. Chelation therapy was provided to the child for the first time in 1999 with DMSA by a biomedical team that included a local doctor. The treatment outcomes will be reported in a separate study.

Fig. 6
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Discussion

The present study investigated the integrity of the auditory neural conducting system of the eighth nerve, pons, and midbrain in a large number of chronically Pb-exposed children by using field measurements of BAERs. The averaged neural transmission times as reflected by wave peak latencies of the BAERs have been reported to have considerable utility in neurotoxicity testing and in diagnosing Pb-induced neurological impairment. 23,26 The results demonstrate some evidence of abnormal Pb-induced neural conduction delays in individual children. However, the study group showed a remarkable overall neurobiological stability in a condition of severe, chronic, pediatric Pb intoxication without measurable impairment to brainstem auditory nuclei and tracts, as reflected in neurophysiological conduction times. Most children in the study areas with Pb body burdens in the most severe CDC classifications, IV and V, generally presented with normal neural transmission function in the brainstem auditory system. This is in marked contrast to some earlier studies that have associated impaired hearing and abnormal auditory brainstem conduction with Pb-poisoning levels as low as 10 to 20 μg/dL. 24,25,33

The threshold level and duration of Pb intoxication necessary to induce neuropathology in children are not well established. Recent reports in the biomedical literature reflect considerable variance in the level of Pb intoxication that is associated with pediatric neurodevelopmental disabilities. Some recent studies have reported brainstem neuropathology, as reflected in BAER neurophysiological recordings, in children with PbB levels less than the CDC-designated Pb intoxication levels. 25,27,33 According to the World Health Organization biological limits for Pb intoxication, PbB levels of 20 to 40 μg/dL are considered potentially harmful to the developing nervous system. The CDC, on the other hand, has revised its Pb toxicity threshold, or action line, downward from 25 μg/dL to 10 μg/dL as a result of studies that indicate neurological impairment at low Pb exposure levels (CDC, 1991). Children in the CDC IV (45–69.9 μg/dL) and CDC V (>70 μg/dL) PbB level classifications require immediate medical and environmental intervention, including chelation therapy to prevent or reduce central nervous system damage (CDC, 1991). The 69 children in the CDC IV and V classifications in the present study would be expected to show aberrant BAER parameters, particularly in neural conduction time. Normal neural conduction in the brainstem auditory tract requires intact neurons and synaptic clusters from the eighth cranial nerve to the pons and midbrain nuclei.

The absence of indications of functional neurobiological and morphological abnormality in the BAERs of the Pb-intoxicated children in this study is not fully understood. There were no known dietary factors in the study group that may have afforded protection against the generalized effects of plumbism. Nor were there any known natural or herbal folk remedies administered by the parents for medical intervention. Some of the children regularly consumed milk or milk-based liquids, but none received regular calcium supplements before the visit of our medical team. It is significant that the Pb intoxication found in the children of this study is chronic and is likely to have begun in utero. In this study, highly elevated PbB levels were found over the entire age range of the children receiving BAER tests.

Some individuals in the study group with CDC IV and V levels of Pb intoxication were found to have neurological involvement (eg, case 1), but this finding was not consistent in the study group. The microcephaly and learning disability observed in case 1, for example, may be related to Pb intoxication. On the other hand, the neurological involvement observed in this patient may also have been the result of medical conditions other than Pb poisoning, such as genetic disorders or prenatal exposure to other environmental toxicants, for example, mercury or cadmium.

It is important to ascertain with some degree of certainty whether BAER measures can be used effectively as a clinical biomarker for Pb neurotoxicity. For example, Rothenberg et al 27 and Schnaas et al 16 have reported abnormalities in BAER responses from children who had been exposed to Pb prenatally. Closer examination of the data from these and some earlier studies that reported abnormal BAERs in children with low PbB levels revealed several confounding factors and raised questions as to the validity of reported findings. In one widely cited study, for example, abnormal BAER absolute peak latencies were not actually measured but extrapolated from earlier data. 22 Furthermore, that study reported no abnormalities in the interpeak latencies, which are more indicative of neurological involvement than are measures of absolute peak latencies. 22 Prolongation of absolute peak latencies may be more a function of peripheral hearing deficits caused by conditions such as otitis media and impacted cerumen that are common in some children than a sign of neuro-ototoxicity. Similarly, in a more recent study, Osman et al 33 reported to have found evidence of Pb-induced impairment of auditory receptor and neural function in children with PbB levels at or below 10 μg/dL (CDC I classification). However, their data showed BAER results that indicated only “a tendency toward increased latencies for waves I, III, and V in children with the highest Pb level,”(ie, 28.1 μg/dL), and the investigators presented no evidence of measured abnormalities. 33 Furthermore, their reported abnormal absolute latency prolongation of only 0.1 ms for waves I, III, and V is within the range of normal clinical variability, and the study revealed no significant relation between PbB and the BAER interpeak intervals at low or high PbB levels. The study by Osman et al 33 also reported significant Pb-induced peripheral hearing impairment in children that may be the basis for their reported abnormal BAERs, but their data showed auditory thresholds that were within the range of normal clinical variability as established by international audiological standards.

The wave I through V interpeak latency interval of the BAER is the most widely used measure of neural conduction from the proximal eighth nerve through the ascending tracts and nuclei of the pons and lower midbrain. Eighth-nerve lesions and lower ipsilateral pontine damage are associated with prolongation of the wave I through III interpeak latency, whereas increases in the wave III through V interpeak interval may indicate mesencephalic lesions. The presence and latency of wave VI were added to the conventional BAER clinical components in this investigation for further analysis of the functional integrity of the higher ascending auditory tract in the most severely Pb-poisoned children. 32 Although the absence of wave VI may not be indicative of neurological impairment because it is also absent in a significant percentage of healthy persons, its presence with a normal latency in patients with severe Pb intoxication suggests functional neural conduction in the region of the inferior colliculus and medial geniculate body. The children in the CDC IV and V classifications revealed wave VI mean latencies within the normal range, suggesting normal neural conduction and synaptic function in the auditory neurons of the midbrain and no discernible neurobiological effects of Pb intoxication.

Both acute and chronic forms of Pb poisoning are generally associated with a broad spectrum of neurological impairments, including general encephalopathy, sensory-motor dysfunction, and learning disabilities. In the developing central nervous system, Pb exposure disrupts calcium-regulated intracellular activity, including protein kinase C regulation at the synapse, and reduces cellular enzyme activity below critical levels. 34,35 Impaired synaptogenesis and mitochondrial function, as well as diminished axon arborizations and segmental demyelination, are also associated with Pb intoxication. 24,36,37 The neurons of the brainstem are believed to be particularly targeted by Pb, with the result being the impairment of sensory-motor functions, including a breakdown in neural conduction times and synaptic volume responses similar to that seen in neurodegenerative diseases such as multiple sclerosis. 38–40 The BAERs recorded from the highly Pb-intoxicated children in the study group of this investigation, however, did not exhibit temporal or morphological patterns similar to those observed in children with neurodegenerative diseases. Nor was there generalized evidence of the neuropathology and motor dysfunction typically associated with Pb-induced neurological impairment.

Several recent investigations have shown evidence of polymorphisms in genetic susceptibility to Pb intoxication. 17–19,41 These studies show evidence of a specific variant of gamma-aminolevulinic dehydratase in some patients with high PbB levels. However, although genetic polymorphism may account for an increased susceptibility to Pb intoxication, it may not explain the absence of abnormal brainstem neural conduction function and gross neurological impairment in cases of extreme pediatric plumbism.

It is possible that the BAER tests used in standard clinical neurophysiology may not be an exceptionally sensitive biomarker for Pb neurotoxicity and that cortical evoked potentials might be more effective as a diagnostic tool. It is also possible that neurocognitive function may be impaired in children of this study without associated neuromotor or neurosensory deficits. In a previous investigation in the same study area, a number of the children were found to exhibit neurocognitive dysfunction without evidence of major neuromotor and neurosensory involvement, thus suggesting Pb-induced cerebral impairment. 42

In conclusion, the results of this study demonstrated extensive Pb intoxication in children who live in an area of widespread Pb contamination from Pb-glazing occupations. However, the children in the study areas showed remarkable neurophysiological responses to chronic Pb intoxication and a higher threshold for BAER aberrations. These findings challenge the prevailing dogma regarding the invariant neurotoxicity of high Pb body burdens. Extensive neurophysiological testing of specific neural tracts in children with CDC IV and V levels of Pb intoxication did not show the type of brainstem neural conduction abnormalities that have been associated with Pb intoxication in the existing medical literature. The apparent neurobiological stability in the condition of high Pb body burden for years with no clinically observable neurosensory or neuromotor abnormality in some of the children of this study group is worthy of further study. Additional investigations, including longitudinal studies, are needed to determine the nature and duration of the observed neurobiological responses to severe Pb intoxication, as well as possible undetected, subclinical, or inconspicuous brainstem neurophysiological effects of Pb exposure. Medical care and chelation therapy are recommended for all children in the study area with elevated PbB levels.

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Acknowledgments

This study was conducted under the auspices of Harvard University and the Universidad San Francisco De Quito Medical School (USFQ) in Quito, Ecuador. The study was approved by the Human Studies Committee of USFQ. The author appreciates the support of Dr Fernando Ortega, Ecuadorian physician to the project; Dr Leo H. Buchanan, medical audiologist and behavioral scientist to the project; Dr Gonzalo Mantilla, MD, Dean of the Medical School at USFQ; and Dr Keith Chiappa, neurophysiologist at the Massachusetts General Hospital. Prof Erik Borg Överlakare, Örebro Hospital, Sweden, is thanked for helpful comments and suggestions. Anthony B. Jacobs is thanked for excellent technical assistance. We are also grateful to Dr Howard Hu, Chitra Amarasiriwardena, and Nicoli Lupoli of the Channing Trace Metals Laboratory, Harvard School of Public Health, and Dr Nader Rifai, of Boston Children’s Hospital Medical Laboratories, for laboratory support.

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