Low-level Exposure to Multiple Metals: Effects on Cognition and Behavior

描述（由申请人提供）：在世界范围内，数以百万计的儿童暴露于有毒金属，包括铅（Pb）、砷（As）、镉（Cd）和锰（Mn），对他们的健康和发展产生重要影响。研究结果证实了接触单一有毒金属与儿童神经行为缺陷之间的联系。然而，金属暴露很少单独发生。然而，迄今为止，很少有研究调查有毒金属对认知缺陷或行为问题的相互作用，结果往往好坏参半。人们对多种金属接触对儿童发育的长期影响也知之甚少。因此，数据的缺乏和方法的限制使这一领域无法为保护儿童和儿科实践提出合理的建议。本研究的长期目标是了解低水平接触多种有毒金属如何影响儿童和青少年的神经行为结果，确定金属对儿童结果的潜在协同效应。本研究的目的是确定儿童接触多种金属如何影响儿童中期的特定认知功能和行为。拟议的研究是一项纵向队列研究，将在乌拉圭蒙得维的亚进行，并以先前对一年级儿童的研究为基础。这项研究的重点是砷、镉、锰和铅，因为这些物质在环境和从乌拉圭儿童身上收集的生物样本中以生物学相关的水平存在。中心假设是，在低暴露范围内，随着时间的推移，较高浓度的砷、镉、锰和铅将单独与较差的认知和行为有关，并且共同暴露于这些金属将对神经行为结果产生累加性或乘法性的负面影响。本研究的具体目的是：1)描述长期暴露于砷、镉、锰和铅的趋势和可变性；2)表征金属的身体负担与特定认知功能缺陷的关联程度；3)表征金属与报告和观察到的问题行为的关联程度。研究人群将由约760名儿童组成。该研究采用交错设计，包括：1)对在之前的两项研究（2010-2013年）中被评估为一年级的儿童进行随访；2)对一年级的儿童进行登记并对其他儿童进行随访。每年收集头发和血液样本，并在一、三、五年级对儿童的认知和行为进行评估。这种方法是创新的，因为与之前的研究相比，它采用纵向方法来检查环境中低水平多种金属之间的相互作用，并采用特定的过程导向的认知结果，而不是智商，这是一种总结性测量。这项研究的重要之处在于它有助于宣传与接触多种有毒金属有关的健康风险，并可能有助于制定预防或减轻接触造成的发育后果的办法。

DESCRIPTION (provided by applicant): Worldwide, millions of children are exposed to toxic metals, including lead (Pb), arsenic (As), cadmium (Cd), and manganese (Mn), with important consequences for their health and development. Research findings confirm the association between exposure to single toxic metals and neurobehavioral deficits in children. However, metal exposures rarely occur in isolation. Nevertheless, few studies to date have examined interactions among toxic metals on cognitive deficits or behavioral problems, often with mixed results. There is also little under- standing of the long-term consequences of multiple metal exposures on child outcomes. Thus, the scarcity of data and methodological limitations have kept this field from making sound recommendations for the protection of children and pediatric practice. The long-term goal of this research is to understand how low-level exposure to multiple toxic metals affects neurobehavioral outcomes across childhood and adolescence, identifying potential synergistic effects of metals on children's outcomes. The objective of the proposed study is to determine how children's exposure to multiple metals affects specific cognitive functions and behavior through middle child- hood. The proposed study is a longitudinal cohort study that will take place in Montevideo, Uruguay and builds on previous research in 1st grade children. The study focuses on As, Cd, Mn, Pb because these occur at biologically relevant levels in the environment and biological samples collected from the Uruguayan children. The central hypothesis is that within low range of exposures, higher concentrations of As, Cd, Mn and Pb will be individually associated with poorer cognition and behavior over time, and that co-exposure to these metals will produce additive or multiplicative negative effects on neurobehavioral outcomes. The specific aims of this study are to: 1) describe the trends and variability of the long-term exposure to As, Cd, Mn and Pb, 2) characterize the extent to which body burden of the metals is associated with deficits in specific cognitive functions, and 3) characterize the extent to which the metals are associated with reported and observed problem behaviors. The study population will consist of ~760 children. The study has a staggered design, entailing: 1) the follow-up of children who had been evaluated as 1st-graders in 2 previous studies (years 2010-2013), and 2) the enrollment in 1st grade and follow-up of additional cohorts of children. Hair and blood samples will be collected yearly, and children's cognition and behavior will be evaluated in 1st, 3rd and 5th grade. This approach is innovative because, in contrast to previous studies, in employs a longitudinal approach to examine interactions among multiple metals that occur at low levels in the environment, and employs specific process-oriented cognitive outcomes as opposed to IQ, which is a summative measure. This research is significant in its contribution to the communication of health risks associated with exposure to multiple toxic metals, and in its potential contribution to approaches that will prevent or alleviate the developmental consequences of exposure.