Improving Equitability and Inclusion for Testing and Detection of Lead Poisoning in US Children.

Policy Points Child lead poisoning is associated with socioeconomic inequity and perpetuates health inequality. Methods for testing and detection of child lead poisoning are ill suited to the current demographics and characteristics of the problem. A three-pronged revision of current testing approaches is suggested. Employing the suggested revisions can immediately increase our national capacity for equitable, inclusive testing and detection. ABSTRACT: Child lead poisoning, the longest-standing child public health epidemic in US history, is associated with socioeconomic inequity and perpetuates health inequality. Removing lead from children's environments ("primary prevention") is and must remain the definitive solution for ending child lead poisoning. Until that goal can be realized, protecting children's health necessarily depends on the adequacy of our methods for testing and detection. Current methods for testing and detection, however, are no longer suited to the demographics and magnitude of the problem. We discuss the potential deployment and feasibility of a three-pronged revision of current practices including: 1) acceptance of capillary samples for final determination of lead poisoning, with electronic documentation of "clean" collection methods submitted by workers who complete simple Centers for Disease Control and Prevention-endorsed online training and certification for capillary sample collection; 2) new guidance specifying the analysis of capillary samples by inductively coupled plasma mass spectrometry or graphite furnace atomic absorption spectrometry with documented limit of detection ≤0.2 µg/dL; and 3) adaptive "census tract-specific" universal testing and monitoring guidance for children from birth to 10 years of age. These testing modifications can bring child blood lead level (BLL) testing into homes and communities, immediately increasing our national capacity for inclusive and equitable detection and monitoring of dangerous lower-range BLLs in US children.

Estimating the proportion of bioaccessible lead (BaPb) in household dust wipe samples: a comparison of IVBA and PBET methods.

Established methods for using standardized dust wipes to collect and measure total lead in household dust are readily available but the use of dust wipes to measure bioaccessible lead (BaPb) is less clear. This study compared two in vitro methods for estimating the proportion of BaPb in dust collected into dust wipes including the US-EPA's in-vitro bioaccessible assay (IVBA) method at two pH (1.5 and 2.5) values; and the physiologically based extraction test (PBET 2.5 pH). Two types of simulated household dust samples (Pb-soil contaminated and Pb-paint contaminated) each with three Pb concentrations were created. Equal amounts of simulated dust were applied to a smooth surface and collected following the standard EPA dust wipe protocol and were analyzed for BaPb and total Pb (ASTM-E1644-17, ICP-OES). Estimated BaPb levels differed significantly by the method of extraction. Mean percent BaPb were IVBA pH 1.5, > 90% (Pb-paint) and 59-63% (Pb-soil); IVBA pH 2.5 78-86% (Pb-paint) and 45-50% (Pb-soil); PBET pH 2.5 56 to 61% (Pb-paint) and 41-50% Pb-soil). Particularly for lead-paint contaminated dust, PBET showed significantly greater discrimination as suggested by the broader range of BaPb values and closer approximation to total lead concentrations in simulated household dust samples.

A Comparison of Child Blood Lead Levels in Urban and Rural Children Ages 5-12 Years Living in the Border Region of El Paso, Texas.

Lead exposure is an unresolved pediatric health risk and disproportionately affects children in lower-income neighborhoods. Residences with children younger than age 5 years are the focus of mitigation policies; however, studies have shown that older children between the ages of 5 and 12 years also are at risk of central nervous system effects. Whether historically contaminated neighborhoods present ongoing risk to older children also is of concern. This study compared the blood lead levels (BLLs) of older children from an historically contaminated urban neighborhood to those of demographically matched children from a nearby rural locale and predicted significantly higher BLLs in the urban children. The study included 222 children aged 5-12 years, 111 from the urban neighborhood and 111 from local rural townships, matched for age, sex, race/ethnicity, and family income. Blood lead, cadmium, and mercury were measured using inductively coupled plasma mass spectrometry. General linear models tested whether geographic location (urban vs. rural) predicted child heavy metal levels, controlling for sex and age. Only location predicted only child BLL (R2= 0.36); children living in the urban setting had significantly higher BLLs as compared with matched rural township children (F = 125, df220,2, p <0.001). Neighborhoods with a history of lead contamination can present current risk of lead exposure for older children between the ages of 5 and 12 years, as well as for infants and toddlers. More studies are needed to better characterize the risk of lead exposure to older children, particularly in lower-income neighborhoods with a history of lead contamination.

A comparison of arsenic exposure in young children and home water arsenic in two rural West Texas communities.

BACKGROUND: In a previously conducted Health Impact Assessment of a well-water dependent southwest community, arsenic (As) levels greater than the EPA Maximum Contaminant Level (10 µg/L) were identified in home water samples. The goals of this study were to test whether children from the previously studied well-water dependent community (Community 1) had higher blood As levels than children from a demographically similar and geographically nearby community dependent on a municipal water supply (Community 2); to test whether home water As levels predicted child As blood levels; and to examine how child As blood levels changed over time. METHODS: This was an observational study of 252 children aged 4 to 12 years from two communities. Children were recruited through elementary schools and tested during the school day; 204 children participated in follow-up testing. Home water samples were collected according to U.S. Environmental Protection agency recommended procedures. Child heavy metal blood levels and home water sample heavy metal levels were analyzed using inductively coupled plasma mass spectrometry. General linear regression analysis was used to test the influence of community on child As levels, and to examine the contribution of home water As levels to child blood As levels. RESULTS: Arsenic was detectable in all children tested. Blood levels ranged from 0.09-2.61 µg/dL; approximately 31% of children tested at Time I (79/252) had blood As values above the current acceptable limit (1.2 µg/dL). Approximately 8% of household water samples (6/76) had As levels higher than 10 µg/L. Community did not predict child blood As levels; seasonal effects differed by Community. At Time II, child blood As levels were higher in Community 2 than in Community 1. CONCLUSION: A large proportion of children in the communities tested had As exposure. Home water As levels did not predict child blood As levels. Fluctuating child blood As levels by season and over time suggested the contribution of multiple factors and the need for further studies.

A Comparison of Water-Related Perceptions and Practices Among West Texas and South New Mexico Colonia Residents Using Hauled-Stored and Private Well Water.

In Texas, Arizona, and New Mexico, colonias refer to unincorporated rural settlements along the U.S.­Mexico border. Colonias lack governance and public services normally provided by local government (Ward, 1999). Residents typically rely on well water or hauled water stored in above-ground containers. This study attempted to quantify and compare water-related perceptions and practices of colonia residents. No significant differences were observed between colonia residents using well water versus hauled-stored water for water quality perceptions and water use practices. Most, however, had negative perceptions of their water supply; a majority perceived daily water supplies as not potable. Significant paradoxical discrepancies between perceptions and practice were identified. This study adds to a small but growing literature on subjective dimensions of quality of life indicators for colonia residents. Additional studies are needed to quantify the type and level of health risks posed by compromised water supplies for this vulnerable population. Understanding differences in perceptions and practices associated with water sources could help to identify which subpopulations of colonia residents are in greatest need of water infrastructure or remediation.

Early chronic lead exposure reduces exploratory activity in young C57BL/6J mice.

Research has suggested that chronic low-level lead exposure diminishes neurocognitive function in children. Tests that are sensitive to behavioral effects at lowest levels of lead exposure are needed for the development of animal models. In this study we investigated the effects of chronic low-level lead exposure on exploratory activity (unbaited nose poke task), exploratory ambulation (open field task) and motor coordination (Rotarod task) in pre-adolescent mice. C57BL/6J pups were exposed to 0 ppm (controls), 30 ppm (low-dose) or 230 ppm (high-dose) lead acetate via dams' drinking water administered from birth to postnatal day 28, to achieve a range of blood lead levels (BLLs) from not detectable to 14.84 µg dl(-1) ). At postnatal day 28, mice completed behavioral testing and were killed (n = 61). BLLs were determined by inductively coupled plasma mass spectrometry. The effects of lead exposure on behavior were tested using generalized linear mixed model analyses with BLL, sex and the interaction as fixed effects, and litter as the random effect. BLL predicted decreased exploratory activity and no threshold of effect was apparent. As BLL increased, nose pokes decreased. The C57BL/6J mouse is a useful model for examining effects of early chronic low-level lead exposure on behavior. In the C57BL/6J mouse, the unbaited nose poke task is sensitive to the effects of early chronic low-level lead exposure. This is the first animal study to show behavioral effects in pre-adolescent lead-exposed mice with BLL below 5 µg dl(-1).

Stability of blood lead levels in children with low-level lead absorption.

Current child blood lead (Pb) screening guidelines assume that blood lead levels (BLLs) are relatively stable over time, and that only youngest children are vulnerable to the damaging effects of lower-range BLLs. This study aimed to test the stability of lower-range (≤ 10 µg/dL) child BLLs over time, and whether lower-range BLLs diminished with age among children aged 6 months to 16 years living in a lower-income neighborhood with a density of pre-1986 housing and legacy contamination. Age, sex, family income, age of residence, and/or residence proximity to point sources of Pb, were tested as potential additional factors. Capillary blood samples from 193 children were analyzed by inductively coupled plasma mass spectrometry (ICPMS). Multiple imputation was used to simulate missing data for 3 blood tests for each child. Integrated Growth Curve models with Test Wave as a random effect were used to test BLL variability over time. Among N = 193 children tested, at Time 1 testing, 8.7% had the BLLs ≥ 5 µg/dL (CDC "elevated" BLL reference value at the time of data collection) and 16.8% had BLLs ≥ 3.5 µg/dL (2021 CDC "elevated" BLL reference value). Modeling with time as a random effect showed that the variability of BLLs were attributable to changes within children. Moreover, time was not a significant predictor of child BLLs over 18 months. A sex by age interaction suggested that BLLs diminished with age only among males. Of the additional environmental factors tested, only proximity to a major source of industrial or vehicle exhaust pollution predicted child BLL variability, and was associated with a small, but significant BLL increase (0.22 µg/dL). These findings suggest that one or two BLL tests for only infants or toddlers are insufficient for identifying children with Pb poisoning.

An interdisciplinary team-based approach for significantly reducing lower-level lead poisoning in U.S. children.

Child lead poisoning damages central nervous system, immune, and renal function, and is the longest-standing public health epidemic in U.S. history. While primary prevention is the ultimate goal, secondary intervention is critical for curbing effects among children already exposed. Despite the lowering of child blood lead level (BLL) reference value in 2012 and again in 2021, few changes to secondary intervention approaches have been discussed. This study tested a novel interdisciplinary approach integrating ongoing child BLL-monitoring with education and home mitigation for families living in neighborhoods at high-risk of child lead exposure. In children ages 6 months to 16 years, most of whom had lowest range exposures, we predicted significantly reduced BLLs following intervention. Methods: Twenty-one families with 49 children, were offered enrollment when at least 1 child in the family was found to have a BLL > 2.5 µg/dL. Child BLLs, determined by ICPMS, were monitored at 4- to 6-month intervals. Education was tailored to family needs, reinforced through repeated parent engagement, and was followed by home testing reports with detailed case-specific information and recommendations for no-cost/low-cost mitigation. Results: Ninety percent of enrolled families complied with the mitigation program. In most cases, isolated, simple-to-mitigate lead hazard sources were found. Most prevalent were consumer products, found in 69% (11/16) of homes. Lead paint was identified in 56% (9/16) of homes. Generalized linear regression with Test Wave as a random effect showed that children's BLLs decreased significantly following the intervention despite fluctuations. Conclusion: Lower-level lead poisoning can be reduced through an interdisciplinary approach that combines ongoing child BLL monitoring; repeated, one-on-one parent prevention education; and identification and no-cost/low-cost mitigation of home lead hazards. Biannual child BLL monitoring is essential for detecting and responding to changes in child BLLs, particularly in neighborhoods deemed high-risk for child lead poisoning.

δ-Aminolevulinic acid dehydratase single nucleotide polymorphism 2 and peptide transporter 2*2 haplotype may differentially mediate lead exposure in male children.

Child low-level lead (Pb) exposure is an unresolved public health problem and an unaddressed child health disparity. Particularly in cases of low-level exposure, source removal can be impossible to accomplish, and the only practical strategy for reducing risk may be primary prevention. Genetic biomarkers of increased neurotoxic risk could help to identify small subgroups of children for early intervention. Previous studies have suggested that, by way of a distinct mechanism, δ-aminolevulinic acid dehydratase single nucleotide polymorphism 2 (ALAD(2)) and/or peptide transporter 2*2 haplotype (hPEPT2*2) increase Pb blood burden in children. Studies have not yet examined whether sex mediates the effects of genotype on blood Pb burden. Also, previous studies have not included blood iron (Fe) level in their analyses. Blood and cheek cell samples were obtained from 306 minority children, ages 5.1 to 12.9 years. (208)Pb and (56)Fe levels were determined with inductively coupled plasma-mass spectrometry. General linear model analyses were used to examine differences in Pb blood burden by genotype and sex while controlling for blood Fe level. The sample geometric mean Pb level was 2.75 µg/dl. Pb blood burden was differentially higher in ALAD(2) heterozygous boys and hPEPT2*2 homozygous boys. These results suggest that the effect of ALAD(2) and hPEPT2*2 on Pb blood burden may be sexually dimorphic. ALAD(2) and hPEPT2*2 may be novel biomarkers of health and mental health risks in male children exposed to low levels of Pb.

Statistical modeling with litter as a random effect in mixed models to manage "intralitter likeness".

"Intralitter likeness," the possibility that the shared genetics and/or maternal environment in multiparous species causes strong similarity for outcome variables in littermates, violates a core statistical assumption, that of observation independence, when littermate outcomes are analyzed. Intralitter likeness has been of major concern to investigators for several decades. Despite consensus and guidance, many research reports in the rodent literature continue to ignore intralitter likeness. A historical review of the literature revealed that the long-preferred solution was to include litter as an effect in statistical models. Limitations in software development and computing capacity prior to 1990, however, appear to have led researchers and guidance authorities to endorse instead the method of using one value per litter. Here, the history of discussions regarding intralitter likeness in developmental neurotoxicological research is reviewed; growing knowledge regarding the biological bases and significance of intralitter likeness is discussed; principles underlying the use of litter as a random effect in mixed models are presented; statistical examples are provided illustrating the advantages and critical importance of including litter as a random effect in mixed models; and results using all data points (all pups from all litters) with litter as a random effect, are compared to results based on random selections of representative littermates. Mixed models with litter included as a random effect have distinct advantages for the analysis of clustered data. Modern computing capacity provides ready accessibility to mixed models for all researchers. Accessibility however does not preclude the need for appropriate expertise and consultation in the use of mixed (hierarchical) models.

Potential frameworks to support evaluation of mechanistic data for developmental neurotoxicity outcomes: A symposium report.

A key challenge in systematically incorporating mechanistic data into human health assessments is that, compared to studies of apical health endpoints, these data are both more abundant (mechanistic studies routinely outnumber other studies by several orders of magnitude) and more heterogeneous (e.g. different species, test system, tissue, cell type, exposure paradigm, or specific assays performed). A structured decision-making process for organizing, integrating, and weighing mechanistic DNT data for use in human health risk assessments will improve the consistency and efficiency of such evaluations. At the Developmental Neurotoxicology Society (DNTS) 2016 annual meeting, a symposium was held to address the application of existing organizing principles and frameworks for evaluation of mechanistic data relevant to interpreting neurotoxicology data. Speakers identified considerations with potential to advance the use of mechanistic DNT data in risk assessment, including considering the context of each exposure, since epigenetics, tissue type, sex, stress, nutrition and other factors can modify toxicity responses in organisms. It was also suggested that, because behavior is a manifestation of complex nervous system function, the presence and absence of behavioral change itself could be used to organize the interpretation of multiple complex simultaneous mechanistic changes. Several challenges were identified with frameworks and their implementation, and ongoing research to develop these approaches represents an early step toward full evaluation of mechanistic DNT data for assessments.

Sex differences in the behavior of children with the 22q11 deletion syndrome.

High rates of psychiatric impairment in adults with 22q11 deletion syndrome (22q11DS, also referred to as DiGeorge or velocardiofacial syndrome) suggest that behavioral trajectories of children with 22q11DS may provide critical etiologic insights. Past findings that report Diagnostic and Statistical Manual (DSM) diagnoses are extremely variable; moreover, sex differences in behavior have not yet been examined. Child Behavior Checklist (CBCL) ratings from 82 children, including 51 with the 22q11DS and 31 control siblings, were analyzed. Strikingly consistent with rates of psychiatric impairment among affected adults, 25% of children with 22q11DS had high CBCL scores for Total Impairment, and 20% had high CBCL Internalizing Scale scores. Males accounted for 90% of high Internalizing scores and 67% of high Total Impairment scores. Attention and Social Problems were ubiquitous; more affected males than females (23% vs. 4%) scored high on Thought Problems. With regard to CBCL/DSM overlap, 20% of affected males as compared with 0 affected females had one or more high CBCL ratings in the absence of a DSM diagnosis. Behaviors of children with 22q11DS are characterized by marked sex differences when rated dimensionally, with significantly more males experiencing Internalizing and Thought Problems. Categorical diagnoses do not reflect behavioral differences between male and female children with 22q11DS, and may miss significant behavior problems in 20% of affected males.

Early chronic exposure to low-level lead alters total hippocampal microglia in pre-adolescent mice.

Developmental lead (Pb) exposure alters brain function through mechanisms that are not yet understood. A previous study showed that early lead exposure reduced microglia number in the dentate gyrus region of the hippocampus. Given the critical role of microglia in brain development, it is important to determine whether these differences are unique to the dentate gyrus, or occur throughout the hippocampus. Unbiased stereology was used to quantify microglia mean cell body number in total hippocampus, and compare the proportion of microglia in the ventral vs. dorsal regions. Total hippocampal volume was also measured and compared. The study included brain tissue from 30 pre-adolescent C57BL/6 J mice, exposed to 30 ppm Pb acetate (n = 10, mean BLL 3.4 µg/dL at sacrifice), 330 ppm Pb acetate (n = 10, mean BLL 14.1 µg/dL at sacrifice), or 0 ppm Pb acetate (n = 10, negative controls). In lead exposed animals, microglia mean cell body number was reduced in total hippocampus; total hippocampal volume was reduced. Importantly, effects in low- and high-dose exposure groups did not differ. Contrary to study hypotheses, the distribution of hippocampal microglia in the ventral vs. dorsal hippocampal regions did not differ. Overall, lowest and higher levels of lead exposure during development had strikingly similar disruptive effects in the neuroimmune system. Studies are needed to determine the immune and other mechanisms responsible for these effects. Future studies would benefit from larger samples to determine whether in fact there is a group by sex interaction driving the effects of early lead exposure on microglia.

Early chronic low-level lead exposure reduced C-C chemokine receptor 7 in hippocampal microglia.

Chronic low-level lead exposure alters cognitive function in young children however the mechanisms mediating these deficits in the brain are not known. Previous studies in our laboratory showed that early lead exposure reduced the number of microglial cells in hippocampus/dentate gyrus of C57BL/6 J mice. In the current study, C-C chemokine receptor 7 (CCR7) and major histocompatibility complex II (MHC II) were examined to investigate whether these neuroimmune factors which are known to trigger cell migration and antigen presentation, were altered by early chronic lead exposure. Thirty-six C57BL/6 J male mice were exposed to 0 ppm (controls, n = 12), 30 ppm (low-dose, n = 12), or 430 ppm (higher-dose, n = 12) of lead acetate via dams' milk from postnatal day (PND) 0 to 28. Flow cytometry was used to quantify cell types and cell surface expression of MHC II and CCR7 in hippocampal and whole brain microglia. Non-parametric independent samples median tests were used to test for statistically significant differences between groups. As compared to controls, CCR7 in hippocampal microglia was decreased in the low-dose group, measured as geometric mean fluorescence intensity (GMFI); in the higher-dose group CCR7+MHC II- hippocampal microglia were decreased. Further analyses revealed that the higher-dose group had decreased percentage of CCR7+MHC II- hippocampal macrophages as compared to controls but increased MHC II levels in CCR7+MHC II+ hippocampal macrophages as compared to controls. It was also noted that lead exposure disrupted the balance of MHC II and/or CCR7 in lead exposed animals. Reduced CCR7 in hippocampal microglia might alter the neuroimmune environment in hippocampi of lead exposed animals. Additional studies are needed to test this possibility.

Early chronic low-level Pb exposure alters global exploratory behaviors but does not impair spatial and object memory retrieval in an object-in-place task in pre-adolescent C57BL/6J mice.

The mechanisms by which early chronic low-level lead (Pb) exposure disrupts the developing brain are not yet understood. Rodent models have provided promising results however behavioral tests sensitive to effects at lowest levels of exposure during development are needed. Preadolescent animals (N=52) exposed to low and higher levels of Pb via lactation from birth to PND 28 completed the Object-in-Place Task of visual spatial and visual object memory retrieval (at PND 28). Generalized linear mixed models were used, controlling for sex and litter as a random effect. As compared with controls, global vertical exploratory behavior (rearing) markedly increased during memory retrieval. The findings suggested that early chronic Pb exposure altered the development of critical exploratory functions needed for learning and survival. Behaviors exhibited in novel spatial and novel object zone perimeters suggested that the Object-in-Place task is a valid measure of visual spatial and visual object memory in pre-adolescent C57BL/6J mice. Additional studies are needed to understand how early chronic low-level lead exposure disrupts the trajectory and possible linkages of critical exploratory and perceptual systems during development.

Lower prepulse inhibition in children with the 22q11 deletion syndrome.

OBJECTIVE: The 22q11 deletion syndrome is associated with a range of possible physical anomalies, probable ongoing learning disabilities, and a specific constellation of neuropsychological deficits, including impairments in selective and executive visual attention, working memory, and sensorimotor functioning. It has been estimated that 25% of the children with 22q11 deletion syndrome go on to develop schizophrenia in late adolescence or adulthood. This is of urgent concern. Specification of early brain network vulnerabilities may provide a basis for early intervention while indicating critical links between genes and severe psychiatric illness. Neuropsychological studies of children with 22q11 deletion syndrome have implicated an array of potentially aberrant brain pathways. This study was conducted to determine whether preattentive processing ("sensorimotor gating") deficits are present in this population. METHOD: The authors administered a test of prepulse inhibition to 25 children with 22q11 deletion syndrome and their 23 sibling comparison subjects, ages 6-13. It was predicted that the children with 22q11 deletion syndrome would have lower prepulse inhibition than the comparison subjects. RESULTS: Prepulse inhibition in the children with 22q11 deletion syndrome (26.06%) was significantly less than that of the sibling comparison subjects (46.41%). Secondary analyses suggested that this decrement did not reflect developmental delay, and lower prepulse inhibition was associated with particular subsyndromal symptoms in some children. CONCLUSIONS: Sensorimotor gating is lower in children with 22q11 deletion syndrome. These findings may indicate specific brain circuits that are anomalous in 22q11 deletion syndrome.

Neuropsychological characteristics of children with the 22q11 Deletion Syndrome: a descriptive analysis.

Previous reports of cognitive functioning in children with the 22q11 Deletion Syndrome have reported marked variability in IQ and achievement subtest scores. Studies have begun to explore neuropsychological function in 22q11 DS however results are inconsistent and the profile incomplete. We assessed 40 children ages 5-12 with 22q11 DS. Consistent with past results, visual-spatial memory was significantly lower than verbal memory. Differentially lowered scores were found only in visual attention, working memory and motor function. Contrary with some past results quantitative, verbal ability, and visual spatial memory scores were within 1 SD from the standardization sample mean. Motor behavior, not typically discussed with regard to 22q11 DS school-age children, may be critical to incorporate in neurocognitive studies of children with 22q11 DS. Implications of these findings are considered with regard to past results.

Olfactory recognition memory is disrupted in young mice with chronic low-level lead exposure.

Chronic developmental lead exposure yielding very low blood lead burden is an unresolved child public health problem. Few studies have attempted to model neurobehavioral changes in young animals following very low level exposure, and studies are needed to identify tests that are sensitive to the neurobehavioral changes that may occur. Mechanisms of action are not yet known however results have suggested that hippocampus/dentate gyrus may be uniquely vulnerable to early chronic low-level lead exposure. This study examined the sensitivity of a novel odor recognition task to differences in pre-adolescent C57BL/6J mice chronically exposed from birth to PND 28, to 0 ppm (control), 30 ppm (low-dose), or 330 ppm (higher-dose) lead acetate (N=33). Blood lead levels (BLLs) determined by ICP-MS ranged from 0.02 to 20.31 µg/dL. Generalized linear mixed model analyses with litter as a random effect showed a significant interaction of BLL×sex. As BLLs increased olfactory recognition memory decreased in males. Among females, non-linear effects were observed at lower but not higher levels of lead exposure. The novel odor detection task is sensitive to effects associated with early chronic low-level lead exposure in young C57BL/6J mice.

δ-Aminolevulinic acid dehydratase single nucleotide polymorphism 2 (ALAD2) and peptide transporter 2*2 haplotype (hPEPT2*2) differently influence neurobehavior in low-level lead exposed children.

Delta-aminolevulinic acid dehydratase single nucleotide polymorphism 2 (ALAD2) and peptide transporter haplotype 2*2 (hPEPT2*2) through different pathways can increase brain levels of delta-aminolevulinic acid and are associated with higher blood lead burden in young children. Past child and adult findings regarding ALAD2 and neurobehavior have been inconsistent, and the possible association of hPEPT2*2 and neurobehavior has not yet been examined. Mean blood lead level (BLL), genotype, and neurobehavioral function (fine motor dexterity, working memory, visual attention and short-term memory) were assessed in 206 males and 215 females ages 5.1-11.8years. Ninety-six percent of children had BLLs<5.0µg/dl. After adjusting for covariates (sex, age and mother's level of education) and sibling exclusion (N=252), generalized linear mixed model analyses showed opposite effects for the ALAD2 and hPEPT2*2 genetic variants. Significant effects for ALAD2 were observed only as interactions with BLL and the results suggested that ALAD2 was neuroprotective. As BLL increased, ALAD2 was associated with enhanced visual attention and enhanced working memory (fewer commission errors). Independent of BLL, hPEPT2*2 predicted poorer motor dexterity and poorer working memory (more commission errors). BLL alone predicted poorer working memory from increased omission errors. The findings provided further substantiation that (independent of the genetic variants examined) lowest-level lead exposure disrupted early neurobehavioral function, and suggested that common genetic variants alter the neurotoxic potential of low-level lead. ALAD2 and hPEPT2*2 may be valuable markers of risk, and indicate novel mechanisms of lead-induced neurotoxicity. Longitudinal studies are needed to examine long-term influences of these genetic variants on neurobehavior.

Networks of attention in children with the 22q11 deletion syndrome.

The 22q11 chromosomal deletion syndrome (22q11 DS) is associated with learning disabilities and a complex neuropsychological profile. Previous findings have suggested that executive attention deficits might underlie other neurocognitive anomalies. We administered the child Attention Network Test (ANT) to 52 children ages 5.0 to 11.5, 32 22q11 DS children (19 girls) and 20 controls (13 girls) and assessed the efficiency of segregated executive, orienting, and alerting networks. We hypothesized that 22q11 DS children have impaired executive network efficiency as compared to control siblings. The internal validity of the child ANT was confirmed for this population. Analysis of variance results showed significant main effects for flanker and cue types and no interaction effect in either 22q11 DS children or control siblings. Compared to control siblings, 22q11 DS children had significantly larger (less efficient) executive network scores, significantly increased errors on only incongruent trials, and a significant correlation between executive network scores and accuracy. The implications of these findings for future neurocognitive studies of 22q11 DS children are considered.