succimer and Cognition-Disorders

Topics: Chelating Agents; Chelation Therapy; Child; Child Development; Child, Preschool; Cognition Disorders; Environmental Exposure; Humans; Lead; Lead Poisoning; Randomized Controlled Trials as Topic; Succimer; Treatment Outcome

Because the toxicological effects of mercury (Hg) are more serious in the developing central nervous system of children than adults, there are growing concerns about prenatal and early childhood Hg exposure. This study examined postnatal methylmercury (MeHg) exposure and cognition and behavior in 780 children enrolled in the Treatment of Lead (Pb)-exposed Children clinical trial (TLC) with 396 children allocated to the succimer and 384 to the placebo groups. Mercury exposure was determined from analyses of blood drawn 1 week before randomization and 1 week after treatment began when succimer had its maximal effect on blood Pb (PbB). The baseline MeHg concentrations were 0.54 microg/L and 0.52 microg/L and post-treatment concentrations were 0.51 microg/L and 0.48 microg/L for placebo and succimer groups, respectively. Because the baseline characteristics in the two groups were balanced and because succimer had little effect on MeHg concentration and no effect on the cognitive or behavioral test scores, the groups were combined in the analysis of MeHg and neurodevelopment. The children's IQ and neurobehavioral performance were tested at age 2, 5 and 7 years. We saw weak, non-significant but consistently positive associations between blood MeHg and IQ test scores in stratified, spline regression and generalized linear model data analyses. The behavioral problem scores were constant or decreased slightly with increasing MeHg concentration. Additional adjustment for PbB levels in multivariable models did not alter the conclusion for MeHg and IQ scores, but did confirm that concurrent PbB was strongly associated with IQ and behavior in TLC children. The effects of MeHg on neurodevelopmental indices did not substantially differ by PbB strata. We conclude that at the present background postnatal MeHg exposure levels of US children, adverse effects on children's IQ and behavior are not detectable.

Topics: Age Factors; Antidotes; Child Behavior Disorders; Child Development; Child, Preschool; Cognition; Cognition Disorders; Female; Humans; Infant; Intelligence; Lead; Lead Poisoning, Nervous System, Childhood; Longitudinal Studies; Male; Mercury Poisoning, Nervous System; Methylmercury Compounds; Neuropsychological Tests; Statistics as Topic; Succimer

Increases in peak blood lead concentrations, which occur at 18-30 months of age in the United States, are thought to result in lower IQ scores at 4-6 years of age, when IQ becomes stable and measurable. Data from a prospective study conducted in Boston suggested that blood lead concentrations at 2 years of age were more predictive of cognitive deficits in older children than were later blood lead concentrations or blood lead concentrations measured concurrently with IQ. Therefore, cross-sectional associations between blood lead and IQ in school-age children have been widely interpreted as the residual effects of higher blood lead concentrations at an earlier age or the tendency of less intelligent children to ingest more leaded dust or paint chips, rather than as a causal relationship in older children. Here we analyze data from a clinical trial in which children were treated for elevated blood lead concentrations (20-44 microg/dL) at about 2 years of age and followed until 7 years of age with serial IQ tests and measurements of blood lead. We found that cross-sectional associations increased in strength as the children became older, whereas the relation between baseline blood lead and IQ attenuated. Peak blood lead level thus does not fully account for the observed association in older children between their lower blood lead concentrations and IQ. The effect of concurrent blood level on IQ may therefore be greater than currently believed.

Topics: Age Factors; Chelating Agents; Child; Child Development; Child, Preschool; Cognition Disorders; Confounding Factors, Epidemiologic; Cross-Sectional Studies; Female; Humans; Intelligence; Lead; Lead Poisoning; Male; Placebos; Succimer

Exposure to lead at levels encountered by urban children impairs cognitive development. An observational study suggested improvement in IQ when blood lead level fell, but the only randomized trial of chelation showed no benefit in IQ.. We did a new analysis of the data from the clinical trial using change in blood lead level as the independent variable. The 741 children began with blood lead levels between 20 and 44 microg/dL, and were 13 to 33 months old at randomization to chelation or placebo. Blood lead levels were measured repeatedly, and cognitive tests were given at baseline, 6 months, and 36 months follow-up.. By 6 months after randomization, blood lead levels had fallen by similar amounts in both chelated and placebo children, despite the immediate drops in the chelated group; there was no association between change in blood lead level and change in cognitive test score. Blood lead levels continued to fall. At 36 months follow-up, in the placebo group only, cognitive test scores had increased 4.0 points per 10 microg/dL fall in blood lead level from baseline to 36 months follow-up and 5.1 points from 6 to 36 months.. The improvement in scores in the placebo group only implies that factors other than declining blood lead levels per se are responsible for cognitive improvement; it is possible but less likely that succimer, the active drug, impairs cognition.

Topics: Chelating Agents; Child Development; Child, Preschool; Cognition Disorders; Double-Blind Method; Female; Humans; Infant; Lead; Lead Poisoning; Male; Neuropsychological Tests; Placebos; Succimer; Treatment Outcome

Lead exposure in childhood lowers IQ scores, but its effect on children's behavior is less clear. Because IQ, per se, affects behavior, measuring the direct effect of lead requires measuring and then adjusting for IQ. In addition, either peak blood lead concentration, usually at 2 years old, or the lower blood lead level measured at school age may be the most relevant. Few studies have all of this information.. The purpose of this work was to differentiate the direct effect of lead on behavior and the indirect effect through IQ and to examine the strength of the association for peak and concurrent blood lead concentration.. Data come from a clinical trial of the chelating drug succimer to prevent cognitive impairment in 780 urban 12- to 33-month-olds with blood lead concentrations of 20 to 44 microg/dL. The children were followed from ages 2 to 7 years. The trial data were analyzed as a prospective observational study.. Blood lead concentration at 2 years old was not associated with Conners' Parent Rating Scale-Revised scores at 5 years of age or Behavioral Assessment Systems for Children scores at 7 years of age. Blood lead level at 7 years of age had direct effects on the Behavioral Assessment Systems for Children behavioral symptoms index, externalizing, and school problems at age 7.. Concurrent blood lead concentration was associated with externalizing and school problems scales at 7 years of age, and the effect was not entirely mediated through the effect of lead on IQ.

Topics: Age Distribution; Causality; Chelating Agents; Child; Child Behavior Disorders; Child, Preschool; Cognition Disorders; Comorbidity; Environmental Exposure; Environmental Monitoring; Epidemiological Monitoring; Female; Follow-Up Studies; Humans; Intelligence; Lead; Lead Poisoning, Nervous System, Childhood; Male; Odds Ratio; Regression Analysis; Succimer; United States; Urban Population

There is growing pressure for clinicians to prescribe chelation therapy at only slightly elevated blood lead levels. However, very few studies have evaluated whether chelation improves cognitive outcomes in Pb-exposed children, or whether these agents have adverse effects that may affect brain development in the absence of Pb exposure.. The present study was designed to answer these questions, using a rodent model of early childhood Pb exposure and treatment with succimer, a widely used chelating agent for the treatment of Pb poisoning.. Pb exposure produced lasting impairments in learning, attention, inhibitory control, and arousal regulation, paralleling the areas of dysfunction seen in Pb-exposed children. Succimer treatment of the Pb-exposed rats significantly improved learning, attention, and arousal regulation, although the efficacy of the treatment varied as a function of the Pb exposure level and the specific functional deficit. In contrast, succimer treatment of rats not previously exposed to Pb produced lasting and pervasive cognitive and affective dysfunction comparable in magnitude to that produced by the higher Pb exposure regimen.. These are the first data, to our knowledge, to show that treatment with any chelating agent can alleviate cognitive deficits due to Pb exposure. These findings suggest that it may be possible to identify a succimer treatment protocol that improves cognitive outcomes in Pb-exposed children. However, they also suggest that succimer treatment should be strongly discouraged for children who do not have elevated tissue levels of Pb or other heavy metals.

Topics: Animals; Arousal; Attention; Chelating Agents; Chelation Therapy; Cognition Disorders; Female; Lead Poisoning; Learning; Rats; Rats, Long-Evans; Succimer; Toxicity Tests

Topics: Chelating Agents; Chelation Therapy; Child; Child Development; Child, Preschool; Cognition Disorders; Double-Blind Method; Humans; Lead; Lead Poisoning; Neuropsychological Tests; Randomized Controlled Trials as Topic; Succimer

Increasing evidence indicates that early low-level lead (Pb) exposure produces enduring cognitive impairment in children, underscoring the need to develop improved therapeutic intervention. Although chelating agents have been shown to effectively reduce body Pb levels, it is not yet known whether this treatment ameliorates Pb-induced cognitive dysfunction. Clinical research in this area is hampered by the need to rely on reductions in blood Pb levels as the index of treatment efficacy, despite the fact that brain Pb level is the exposure parameter of greatest relevance to neurocognitive outcomes. The present studies were designed to provide information that will aid future research in this area in both human and animal models. The objectives of these studies were (1) to evaluate the efficacy of different doses and durations of succimer (meso-2,3-dimercaptosuccinic acid; DMSA) chelation for reducing brain and blood Pb levels and (2) to determine the extent to which blood Pb can serve as a surrogate of brain Pb following chelation. Long-Evans hooded rats were exposed to Pb from birth until day 31 (Study 1) or day 40 (Study 2) of life, followed by oral treatment with a vehicle or one of two succimer regimens for a duration of either 7 or 21 days. Results indicated that 7 days of succimer treatment produced a 1.5- to 2.5-fold greater reduction of Pb in blood than in brain, relative to time-matched vehicle groups. Prolonged treatment (21) days did not further reduce blood Pb levels (relative to 7-day succimer treatment), but did produce further reductions in brain Pb level compared to time-matched vehicle groups. Thus, chelation-mediated reductions in brain Pb did not parallel reductions in blood Pb over the course of treatment. While the relevance of these data to humans may be confounded by anatomical and physiological differences between rodents and primates, as well as differences in the metabolism of succimer (DMSA), they suggest that clinical studies should exercise caution when using blood Pb as an index of the efficacy of chelation treatment for reducing brain Pb levels.

Topics: Administration, Oral; Animals; Animals, Newborn; Brain; Brain Chemistry; Chelating Agents; Cognition Disorders; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Lead; Lead Poisoning; Male; Random Allocation; Rats; Succimer