The effect of chelation therapy with succimer on neuropsychological development in children exposed to lead.

BACKGROUND: Thousands of children, especially poor children living in deteriorated urban housing, are exposed to enough lead to produce cognitive impairment. It is not known whether treatment to reduce blood lead levels prevents or reduces such impairment. METHODS: We enrolled 780 children with blood lead levels of 20 to 44 microg per deciliter (1.0 to 2.1 micromol per liter) in a randomized, placebo-controlled, double-blind trial of up to three 26-day courses of treatment with succimer, a lead chelator that is administered orally. The children lived in deteriorating inner-city housing and were 12 to 33 months of age at enrollment; 77 percent were black, and 5 percent were Hispanic. Follow-up included tests of cognitive, motor, behavioral, and neuropsychological function over a period of 36 months. RESULTS: During the first six months of the trial, the mean blood lead level in the children given succimer was 4.5 microg per deciliter (0.2 micromol per liter) lower than the mean level in the children given placebo (95 percent confidence interval, 3.7 to 5.3 microg per deciliter [0.2 to 0.3 micromol per liter]). At 36 months of follow-up, the mean IQ score of children given succimer was 1 point lower than that of children given placebo, and the behavior of children given succimer was slightly worse as rated by a parent. However, the children given succimer scored slightly better on the Developmental Neuropsychological Assessment, a battery of tests designed to measure neuropsychological deficits thought to interfere with learning. All these differences were small, and none were statistically significant. CONCLUSIONS: Treatment with succimer lowered blood lead levels but did not improve scores on tests of cognition, behavior, or neuropsychological function in children with blood lead levels below 45 microg per deciliter. Since succimer is as effective as any lead chelator currently available, chelation therapy is not indicated for children with these blood lead levels.

Early exposure to lead and juvenile delinquency.

Cross-sectional studies have reported an association between lead (Pb) levels in bone and delinquent behavior in later childhood and adolescence. This is the first prospective longitudinal study of Pb and child development to address this question with comprehensive assessments of toxicant exposure and other developmental cofactors. A prospective longitudinal birth cohort of 195 urban, inner-city adolescents recruited between 1979 and 1985 was examined. Relationships between prenatal and postnatal exposure to Pb (serial blood Pb determinations) and antisocial and delinquent behaviors (self- and parental reports) were examined. Prenatal exposure to Pb was significantly associated with a covariate-adjusted increase in the frequency of parent-reported delinquent and antisocial behaviors, while prenatal and postnatal exposure to Pb was significantly associated with a covariate-adjusted increase in frequency of self-reported delinquent and antisocial behaviors, including marijuana use. Use of marijuana itself by Cincinnati Lead Study (CLS) teens was strongly associated with all measures of delinquent and antisocial behavior. This prospective longitudinal study confirmed earlier clinical observations and recent retrospective studies that have linked Pb exposure with antisocial behavior in children and adolescents. Both prenatal and postnatal exposure to Pb were associated with reported antisocial acts and may play a measurable role in the epigenesis of behavioral problems independent of the other social and biomedical cofactors assessed in this study.

Symptomatic lead poisoning in infancy: a prospective case analysis.

This report of a case of symptomatic lead poisoning in infancy reinforces the need for continued vigilance in screening and the application of effective therapies to prevent serious physiologic, neurocognitive, and behavioral sequelae. Furthermore, this case illustrates the efficacy of repeated courses of outpatient succimer therapy in limiting a rebound in blood lead concentrations.

The relationship between CVLT-C process scores and measures of executive functioning: lack of support among community-dwelling adolescents.

In an effort to characterize how a child goes about learning and recalling information, the developers of the California Verbal Learning Test for Children (CVLT-C) provided normative data related to both learning outcome and learning process. The present study examined the assertion that CVLT-C process indices relate to executive functioning in a sample of community-dwelling adolescents. Contrary to predictions, measures of executive functioning typically correlated poorly with measures of learning process, despite displaying significant correlations with measures of learning outcome. Although further research is recommended, these findings do not support the clinical interpretation of CVLT-C process indices as reflections of executive functioning.

Partial trisomy 1q with growth hormone deficiency and normal intelligence.

We present two sibs with partial trisomy 1 (q31.1-q32.1) due to a familial insertion. Patient 1 is a girl who presented at age 9 months with minor anomalies, short stature, and normal psychomotor development. Karyotype was 46,XX,der(4)ins(4;1) (p14;q31.1q32.1)pat. The father had a balanced inverted insertion of 1q into 4p, with karyotype 46,XY,ins(4;1)(p14;q31.1q32.1). At age 5 years, patient 1 was found to have short stature with documented growth hormone deficiency and ectopic pituitary. Her growth velocity responded well to treatment with growth hormone. Cognitive testing at 5 9/12 years showed normal intelligence with an IQ of 90. Patient 2, the brother of patient 1, presented with intrauterine growth retardation. He has the same chromosomal insertion as his sister, with partial trisomy 1q. We suggest that there is a recognizable phenotype of trisomy 1(q31.1-q32.1) which includes prenatal and postnatal growth retardation, narrow palpebral fissures, microphthalmia, microstomia, pituitary abnormalities, and normal intelligence in some individuals.

Lead exposure and the motor developmental status of urban six-year-old children in the Cincinnati Prospective Study.

The relationship between asymptomatic lead exposure and subtle deficits in intellectual attainment has been relatively well established by modern studies. However, neuromotor performance has rarely been the focus of these investigations. It was postulated that motor developmental outcomes may be more sensitive indicators of lead's adverse effects on the central nervous system as they are probably less confounded with social factors than cognitive and academic outcomes. A comprehensive neuromotor assessment battery was administered to 245 six-year-old urban inner-city children enrolled in the Cincinnati Lead Study. These children have been followed since birth with quarterly assessments of blood lead concentrations, medical status, and neurobehavioral development. Prior to covariate adjustment, neonatal, but not prenatal blood lead levels were associated with poorer scores on assessments of bilateral coordination, upper-limb speed and dexterity, and a composite index of fine-motor coordination. Averaged postnatal blood lead levels were also associated with lower scores on the aforementioned subtests as well as a measure of visual-motor control. Following statistical adjustment for covariates, neonatal blood lead levels were associated with poorer performance on a measure of upper-limb speed and dexterity and the fine-motor composite. Postnatal blood lead levels remained significantly associated with poorer scores on measures of bilateral coordination, visual-motor control, upper-limb speed and dexterity, and the fine-motor composite. Low to moderate lead exposure is associated with moderate deficits in gross and especially fine-motor developmental status. Results of this study provide support for recent initiatives to reduce the exposure of children to sources of environmental lead.

Functional implications of postural disequilibrium due to lead exposure.

Measurement of postural equilibrium has been employed as an indirect indicator of functional status of the nervous systems of 109 children (mean age: 5.8 +/- 0.78 years) from the Cincinnati Lead Program Project. The geometric mean blood lead for the first five years of life (PbB05) was 11.9 +/- 1.5 micrograms/dL. Postural sway associated with upright balance was noninvasively quantitated with a microprocessor-based force platform and four tasks performed for 30 sec each by the subjects. A covariate-adjusted multiple regression analysis showed statistically significant associations between PbB05 and the postural sway for the task requiring primarily vestibular and/or proprioceptive systems input, implying potential functional impairment. These findings raised several new issues which are addressed here: (1) A dynamic task has been developed to further test the effect of perturbing those afferents' functional capabilities. (2) A method has been developed to quantitate the stability boundary of each subject to better characterize the limits of functionally-safe postural sway. (3) There is a need to perform the postural sway in a shorter duration than 30 sec so that children younger than five years of age can be tested for early identification of Pb-induced functional impairment of postural equilibrium.

The developmental consequences of low to moderate prenatal and postnatal lead exposure: intellectual attainment in the Cincinnati Lead Study Cohort following school entry.

In a further follow-up study of the Cincinnati Lead Study Cohort, 253 children were administered the Wechsler Intelligence Scale for Children-Revised (WISC-R) at approximately 6.5 years of age. Postnatal blood lead concentrations were inversely associated with Full-Scale (FSIQ) and Performance IQ (PIQ). Following statistical adjustment for developmental co-factors such as maternal IQ and an assessment of the quality of caretaking in the home environment, a statistically significant relationship remained between postnatal blood lead concentrations and PIQ. Further statistical analyses suggested that averaged lifetime blood lead concentrations in excess of 20 micrograms/dL were associated with deficits in PIQ on the order of approximately 7 points when compared to children with mean concentrations less or equal to 10 micrograms/dL. These results are discussed in terms of their consistency with other similar studies as well as their internal consistency with earlier reports on this cohort. The findings of this investigation support recent initiatives in the United States to reduce the exposure of children to environmental lead.

Lead exposure and the central auditory processing abilities and cognitive development of urban children: the Cincinnati Lead Study cohort at age 5 years.

This analysis examined the relationship between lead exposure as registered in whole blood (PbB) and the central auditory processing abilities and cognitive developmental status of the Cincinnati cohort (N = 259) at age 5 years. Although the effects were small, higher prenatal, neonatal, and postnatal PbB levels were associated with poorer central auditory processing abilities on the Filtered Word Subtest of the SCAN (a screening test for auditory processing disorders). Higher postnatal PbB levels were associated with poorer performance on all cognitive developmental subscales of the Kaufman Assessment Battery for Children (K-ABC). However, following adjustment for measures of the home environment and maternal intelligence, few statistically or near statistically significant associations remained. Our findings are discussed in the context of the related issues of confounding and the detection of weak associations in high risk populations.

Lead exposure and growth in the early preschool child: a follow-up report from the Cincinnati Lead Study.

This report is a follow-up of an earlier study of the effects of low to moderate prenatal and postnatal lead exposure on children's growth in stature. Two hundred thirty-five subjects were assessed every 3 months for lead exposure (blood lead level) and stature (recumbent length) up to 33 months of age. Fetal lead exposure was indexed by maternal blood lead level during pregnancy. The adverse effects of lead on growth during the first year of life were reported previously. This analysis covers essentially the second and third years of life. The results indicate that mean blood lead level during this period was negatively associated with attained height at 33 months of age (P = .002). This association was, however, evidenced only among those children who had mean blood lead levels greater than the cohort median (greater than or equal to 10.77 micrograms/dL) during the 3- to 15-month interval. The results also suggest that the effect of lead exposure (both in utero as well as during the first year of life) are transient provided that subsequent exposure to lead is not excessive. It appears that maintaining an average blood lead level of 25 micrograms/dL or more during the second and third year of life was detrimental to the child's attained stature at 33 months of age. Approximately 15% of this cohort experienced these levels of lead exposure. Continued follow-up of this cohort will reveal whether these lead-related deficits persist and whether they continue to be dependent on the level of exposure in an earlier period.

Lead exposure and the cognitive development of urban preschool children: the Cincinnati Lead Study cohort at age 4 years.

The purpose of this analysis was to determine if significant associations could be observed between prenatal/postnatal blood lead (PbB) levels and the cognitive development of 258 urban, inner-city children at 4 years of age. These children have been followed since birth with frequent assessments of general health, PbB, and neuropsychological status. The Kaufman Assessment Battery for Children (K-ABC) was administered at approximately 4 years of age. Higher neonatal PbB levels were associated with poorer performance on all K-ABC subscales. However, this inverse association was limited to children from the poorest families. Maternal PbB levels were unrelated to 4-year cognitive status. Few statistically significant associations between postnatal PbB levels and K-ABC scales could be found. However, the results did suggest a weak inverse relationship between postnatal PbB levels and performance on a K-ABC subscale which assesses visual-spatial and visual-motor integration skills. In these results we note both contradiction and accord with previously published prospective studies.

Structural equation modeling in environmental risk assessment.

Environmental epidemiology requires effective models that take individual observations of environmental factors and connect them into meaningful patterns. Single-factor relationships have given way to multivariable analyses; simple additive models have been augmented by multiplicative (logistic) models. Each of these steps has produced greater enlightenment and understanding. Models that allow for factors causing outputs that can affect later outputs with putative causation working at several different time points (e.g., linkage) are not commonly used in the environmental literature. Structural equation models are a class of covariance structure models that have been used extensively in economics/business and social science but are still little used in the realm of biostatistics. Path analysis in genetic studies is one simplified form of this class of models. We have been using these models in a study of the health and development of infants who have been exposed to lead in utero and in the postnatal home environment. These models require as input the directionality of the relationship and then produce fitted models for multiple inputs causing each factor and the opportunity to have outputs serve as input variables into the next phase of the simultaneously fitted model. Some examples of these models from our research are presented to increase familiarity with this class of models. Use of these models can provide insight into the effect of changing an environmental factor when assessing risk. The usual cautions concerning believing a model, believing causation has been proven, and the assumptions that are required for each model are operative.

Lead exposure and neurobehavioral development in later infancy.

A prospective methodology was used to assess the neurobehavioral effects of fetal and postnatal lead exposure during the first 2 years of life. Lead was measured in whole blood prenatally in mothers and at quarterly intervals in the infant. Prenatal blood lead levels were low (mean = 8.0 micrograms/dL). However, approximately 25% of the study infants had at least one serial blood lead level of 25 micrograms/dL or higher during the second year of life. Multiple regression and structural equation analyses revealed statistically significant relationships between prenatal and neonatal blood lead level and 3- and 6-month Bayley Mental and/or Psychomotor Development Index. However, by 2 years of age, no statistically significant effects of prenatal or postnatal lead exposure on neurobehavioral development could be detected. Data consistent with the hypothesis that a postnatal neurobehavioral growth catch-up occurred in infants exposed fetally to higher levels of lead are presented.

Lead effects on postural balance of children.

The postural sway responses of 63 children with a mean age of 5.74 years were quantified with a Force Platform technique. The average maximum (max) blood lead (PbB) of these children during the first 5 years of life was 20.7 micrograms/dL (range 9.2 to 32.5). The backward stepwise regression analysis for sway area response during the eyes-closed, no-foam test with all the covariates and confounders and the PbB parameters showed a significant relationship with peak or max PbB during the second year of life. These results are consistent with our previous study with a smaller group of children. The data have been analyzed to provide some insight into the role of various afferent for the maintenance of postural balance. The results suggests a hypothesis that if the max PbB had caused some level of impairment in the functional capacities or interconnectivity of the vestibular and/or proprioception systems at 2 years of age, then it is reasonable to assume that the redundancy in the postural afferent systems would naturally adapt to rely more on the remaining intact afferent system (in this case, vision).

Lead exposure in early life: health consequences.

Until very recently it has been considered that of the many manifestations of lead toxicity, those involving the elaboration and function of hemoproteins occur at lower levels of lead exposure than any others. The critical target seems to be the enzyme heme synthetase, which is essential for the insertion of iron into the precursor, protoporphyrin IX. The major consequences of this effect, which have been evaluated in both adults and children, are reduction of circulating levels of hemoglobin and cytochrome P-450-dependent Phase I drug metabolism. Lead clearly inhibits normal hemoprotein function in both respects. The threshold level of lead exposure for these effects seems to be at a circulating lead concentration (PbB) of approximately 30 to 40 micrograms/dL. A growing body of evidence suggests, however, that the functional integrity of the central nervous system is compromised at substantially lower levels of lead exposure, particularly in the human fetus and young child. Early postnatal neurobehavioral development is compromised at maternal or cord PbB of somewhat less than approximately 10 micrograms/dL, a level of lead exposure not uncommon in the general population. Results of more recent cross-sectional and prospective studies indicate that postnatal lead exposure resulting in PbBs as low as 25 micrograms/dL, and probably lower, also are associated with deficits in intellectual attainment, achievement, and behavior. The long-term consequences of these effects remain to be fully evaluated. Little is known concerning basic mechanisms that are responsible for these effects. They may be manifestations of a more basic common effect of lead on cell proliferation and differentiation.