IRS insecticides for malaria control and child neurodevelopment in South Africa

描述(申请人提供)：每年有2.5亿人感染疟疾，导致88万人死亡，主要是五岁以下的非洲儿童。许多疟疾流行国家使用室内残留喷洒(IRS)，即将二氯二苯基三氯乙烷(DDT)或拟除虫菊酯杀虫剂涂抹在房屋的内墙上，以控制疟疾。人们对长期、高水平滴滴涕暴露的意外后果的担忧已导致相当大的国际辩论。例如，《关于持久性有机污染物的斯德哥尔摩公约》旨在禁止滴滴涕，而世界卫生组织和美国国际开发署则促进和/或资助国税局，包括使用滴滴涕。滴滴涕和拟除虫菊酯是昆虫和动物的神经毒物。主要在低到中等水平接触的西方人群中进行的人体研究表明，产前接触DDT及其分解产物DDE可能会对儿童的神经发育产生不利影响。DDT/E暴露还与对甲状腺功能、孕期和出生体重的不利影响以及全球DNA甲基化的变化有关，这可能是神经发育受损的途径。尽管在人类身上几乎没有关于拟除虫菊酯对健康影响的研究，但在啮齿动物身上的研究表明，无论是单独还是与DDT协同作用，都会对神经发育产生有害影响。还没有研究在IRS的背景下评估人类接触DDT和/或拟除虫菊酯对神经发育的影响。我们建议通过研究出生队列研究中暴露于IRS杀虫剂和神经发育之间的关系以及可能的中介因素来解决这些重要的知识差距。我们的目标是招募750名南非农村母亲，并跟踪她们的孩子24个月，前瞻性地评估暴露和神经发育。我们利用了一个自然实验，在这个实验中，海拔的梯度会影响蚊子的存活率，进而影响IRS的使用，但喷药和未喷药的村庄在其他方面是相似的，例如，在人口统计学上。我们拟议的研究将是第一次：1)评估在接受IRS治疗的家庭中孕妇和婴儿接触IRS杀虫剂的水平和决定因素；2)研究非常高的DDT/E和拟除虫菊酯暴露对人类神经发育的影响；3)评估替代IRS杀虫剂的相对和协同健康影响；以及4)评估贫困、营养不良和糟糕的健康状况是否会加剧这些暴露的健康影响。我们将介绍两项对环境健康科学具有更广泛影响的技术：使用PBPK模型来量化婴儿宫内、母乳和其他出生后环境暴露的相对贡献，以及使用最先进的表观遗传学方法来确定环境暴露是否可以改变胎儿组织中的DNA甲基化。这项研究的目的是提供数据，以评估不同疟疾控制方法的风险/效益，并制定适当的干预措施，以减少对孕妇和儿童的接触。

DESCRIPTION (provided by applicant): Every year, 250 million people are infected with malaria, resulting in 880,000 deaths, primarily to African children under age five. Many malaria-endemic countries use Indoor Residual Spraying (IRS), the application of dichlorodiphenyl trichloroethane (DDT) or pyrethroid insecticides to interior walls of homes, to control malaria. Concerns regarding the unintended consequences of chronic, high-level DDT exposure have resulted in considerable international debate. For example, the Stockholm Convention on Persistent Organic Pollutants aims to ban DDT, while the World Health Organization and the U.S. Agency for International Development promote and/or fund IRS, including with DDT. DDT and pyrethroids are neurotoxicants in insects and animals. Human studies, primarily conducted in Western populations with low to moderate levels of exposure, suggest that prenatal exposure to DDT and its breakdown product, DDE, may adversely affect children's neurodevelopment. DDT/E exposure has also been related to adverse effects on thyroid function, gestational duration and birth weight, and changes in global DNA methylation, which could serve as pathways for compromised neurodevelopment. Although there is virtually no research in humans on the health effects of pyrethroids, research in rodents has shown detrimental effects on neurodevelopment both independently and synergistically with DDT. No study has evaluated the impact of human exposure to DDT and/or pyrethroids on neurodevelopment in the context of IRS We propose to address these important knowledge gaps by examining relationships between exposure to IRS insecticides and neurodevelopment, and possible mediators in a birth cohort study. We aim to enroll 750 rural South African mothers and to follow their children for 24 months, assessing exposures and neurodevelopment prospectively. We take advantage of a natural experiment where gradations in altitude impact mosquito survival and, by extension, use of IRS, but sprayed and unsprayed villages are otherwise similar, e.g, demographically. Our proposed study will be the first to: 1) assess levels and determinants of IRS insecticide exposure to pregnant women and infants in IRS-treated homes; 2) study the effects of very high DDT/E and pyrethroid exposures on human neurodevelopment; 3) assess the relative and synergistic health impacts of alternative IRS insecticides; and 4) evaluate whether poverty, malnutrition and poor health potentiate the health effects of these exposures. We will introduce two techniques with wider implications for environmental health science: the use of PBPK models to quantify the relative contributions of in utero, breast milk, and other postnatal environmental exposures in infants, and the use of state-of-the-art epigenetic methods to determine whether environmental exposures can alter DNA methylation in fetal tissue. This study aims to provide data to evaluate the risk/benefit of different methods of malaria control and for the development of appropriate interventions to reduce exposure to pregnant women and children.