Prenatal Exposure to Pesticide Mixtures and Childhood ADHD

产前接触农药混合物与儿童多动症

• 批准号: 9764378
• 负责人: Melissa Furlong
• 金额: $ 8.13万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2020-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9764378
• 关键词: Address; Affect; Age; Agriculture; Algorithms; Arizona; Attention deficit hyperactivity disorder; Behavior Disorders; Biological Markers; Birth Certificates; California; Case-Control Studies; Childhood; Chlorpyrifos; Chronic Disease; Classification; Clinical; Computerized Medical Record; County; Cross-Sectional Studies; Data; Diagnosis; Diagnostic; Environmental Exposure; Epidemiology; Excretory function; Exhibits; Exposure to; Goals; Health; Hour; Humidity; Ingestion; K-Series Research Career Programs; Learning Skill; Life; Link; Literature; Machine Learning; Manuals; Measurement; Measures; Medicaid; Melissa; Mentors; Metabolism; Methods; Modeling; Odds Ratio; Outcome; Parents; Performance; Permethrin; Pesticides; Phase; Phenotype; Population; Pregnancy; Records; Reporting; Research; Sampling; Short-Term Memory; Spottings; Symptoms; Time; Tissues; Toxicant exposure; Toxicology; Training; Urine; aged; agricultural pesticide; base; career; case control; cypermethrin; early childhood; epidemiology study; knowledge base; neurodevelopment; pesticide exposure; prenatal; prenatal exposure; programs; public health relevance; pyrethroid; social; study population; urinary

Prenatal levels of organophosphorus pesticide (OPs) biomarkers have been associated with hallmark symptoms of Attention Deficit Hyperactivity Disorder (ADHD), including deficits in working memory, social responsiveness, and ADHD indices1-4. Cross-sectional studies have also linked concurrent pyrethroid pesticide metabolites with ADHD and ADHD behaviors in children5-7. Toxicology studies report mixture effects for these pesticides on health outcomes8-10. Three major gaps exist in this literature: 1) No studies have evaluated prenatal and childhood exposures to these pesticides and clinical ADHD diagnoses. 2) Prenatal epidemiological studies of OPs/pyrethroids typically rely on urinary DAP biomarkers, which reflect ingestion of both non-toxic metabolites and toxic parent pesticides11. Urinary biomarkers from spot urine samples also do not characterize pregnancy-wide exposures12,13, since OPs and pyrethroids are rapidly metabolized14,15. 3) Studies of pesticide mixtures in epidemiology are scarce, and use of biomarkers for such mixtures analysis is problematic. For instance, administration of chlorpyrifos (an OP) results in increased tissue concentrations of cypermethrin while reducing urinary excretion of the pyrethroid metabolite 3-phenoxbenzoic acid16. Thus, the mixture itself may affect biomarker levels and increase exposure misclassification. A geospatial framework for pesticide exposure can address some of the limitations of urinary biomarkers: exposures from agricultural pesticide applications can be estimated for an entire pregnancy rather than a few days; estimates reflect the toxic parent pesticide rather than non-toxic OP metabolites; and estimates reflect actual exposures rather than a post-metabolism level. However, geospatial (GIS) methods of pesticide exposure assessment for epidemiology in the US have only been done in California17-20, and usually rely on distance-to-field measures. GIS exposure may be enhanced with drift models that incorporate heat, humidity, inversions, atmospheric stability, and wind21,22, while external validity may be increased by studying a population outside of California. We propose to assess the relationship between OPs, pyrethroids, and ADHD in an Arizona population. To identify a study population, we will apply a validated phenotyping algorithm with exceptional diagnostics23 to Arizona Medicaid records to identify 4,000 childhood ADHD cases and 16,000 controls. In the mentored phase, the Candidate will develop geospatial, phenotyping, exposure assessment, mixture modeling (Bayesian Kernel Machine regression [BKMR]), and machine learning skills while constructing the case-control study. In the R00 phase, the Candidate will compare the drift model against traditional distance-to-field measures in a frequentist framework (Aim 2), and model associations between prenatal OP and pyrethroid pesticide mixtures and ADHD with BKMR (Aim 3). These results will expand GIS studies beyond California, contribute to sparse but critical literature on pesticide mixtures and neurodevelopment, and be among the first to report associations between GIS estimates of prenatal pesticide exposures and ADHD case status.

有机磷农药 (OP) 生物标志物的产前水平与标志相关 注意力缺陷多动障碍 (ADHD) 的症状，包括工作记忆、社交能力缺陷 反应能力和 ADHD 指数 1-4。横断面研究也将同时使用的拟除虫菊酯农药与 儿童多动症和多动症行为的代谢物5-7。毒理学研究报告了这些物质的混合效应 农药对健康结果的影响8-10。该文献中存在三个主要差距：1）没有研究评估 产前和儿童时期接触这些农药以及临床多动症诊断。 2) 产前 OP/拟除虫菊酯的流行病学研究通常依赖于尿 DAP 生物标志物，这反映了摄入 无毒代谢物和有毒母体农药11。点尿样本中的尿液生物标志物也可以 不能表征整个怀孕期间的暴露12,13，因为有机磷农药和拟除虫菊酯会快速代谢14,15。 3） 流行病学中农药混合物的研究很少，使用生物标志物进行此类混合物分析的情况也很少。 有问题的。例如，施用毒死蜱（OP）会导致组织浓度增加 氯氰菊酯，同时减少拟除虫菊酯代谢物 3-苯氧苯甲酸 16 的尿排泄。因此， 混合物本身可能会影响生物标志物水平并增加暴露错误分类。地理空间框架 农药暴露可以解决尿液生物标志物的一些局限性： 可以估计整个怀孕期间而不是几天内的农药施用量；估计反映了 有毒母体农药而非无毒OP代谢物；估计反映了实际的风险敞口，而不是 代谢后水平。然而，农药暴露评估的地理空间（GIS）方法 美国的流行病学研究仅在加利福尼亚州进行过 17-20 年，并且通常依赖于现场距离测量。 GIS 暴露可以通过包含热量、湿度、逆温、大气的漂移模型来增强 稳定性和风21,22，而外部效度可以通过研究加利福尼亚州以外的人群来提高。 我们建议评估亚利桑那州人群中 OP、拟除虫菊酯和 ADHD 之间的关系。到 确定研究人群后，我们将应用具有卓越诊断功能的经过验证的表型分析算法23 亚利桑那州医疗补助记录识别出 4,000 例儿童 ADHD 病例和 16,000 例对照。在辅导阶段， 候选人将开发地理空间、表型分析、暴露评估、混合建模（贝叶斯内核 机器回归 [BKMR]），以及构建病例对照研究时的机器学习技能。在R00 阶段，考生将在频率论中将漂移模型与传统的现场距离测量进行比较 框架（目标 2），以及产前 OP 和拟除虫菊酯农药混合物与 ADHD 之间的模型关联 与 BKMR（目标 3）。这些结果将把 GIS 研究扩展到加州以外的地区，有助于稀疏但关键的研究 有关农药混合物和神经发育的文献，并成为第一个报告两者之间关联的人之一 GIS 估计产前农药暴露和 ADHD 病例状况。