Diacetyl in e-cigarette flavorings: Acute and subacute pulmonary effects

电子烟香料中的二乙酰：急性和亚急性肺部影响

• 批准号: 8953056
• 负责人: ROB S MCCONNELL
• 金额: $ 20.63万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-01 至 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8953056
• 关键词: Acute; Adolescent; Adolescent and Young Adult; Aerosols; Age; Amphiregulin; Animals; Awareness; Biological Markers; Breathing; Bronchiolitis Obliterans; Cells; Cellular Phone; Chemicals; Child; Chronic; Clara cell; Cotinine; Data; Data Collection; Development; Diacetyl; Dose; Electronic cigarette; Electronics; Enrollment; Epidermal Growth Factor Receptor; Epithelial; Epithelial Cells; Evaluation; Excretory function; Exposure to; Flavoring; Food; Goals; Guidelines; Health Hazards; Human; IL8 gene; Individual; Ingestion; Intervention; Laboratories; Ligands; Liquid substance; Lung; Lung diseases; Marketing; Measurement; Measures; Nicotine; Nicotine Dependence; Nitric Oxide; Obstructive Lung Diseases; Outcome; Persons; Population; Proteins; Public Health; Publishing; Pulmonary Function Test/Forced Expiratory Volume 1; Records; Regulation; Reporting; Research; Respiratory physiology; Role; Running; Safety; Serum; Solutions; System; Testing; Time; Tobacco; Toxic effect; Toxin; Ultrafine; aerosolized; airway inflammation; base; design; diketone; emerging adult; experience; food preparation; hazard; innovation; lung injury; multidisciplinary; public health relevance; respiratory; respiratory health; respiratory toxin; response; vaping

 DESCRIPTION (provided by applicant): Flavorings in liquids used in electronic nicotine delivery systems (ENDS) are a largely unrecognized potential respiratory hazard. There are thousands of such flavors in commercial use in ENDS, including a large proportion of sweet or creamy flavored ENDS solutions (among the most popular flavorings), used in marketing to children and emerging adults. Several diketone compounds (including diacetyl and 2,3-pentanedione), which are "generally recognized as safe" for ingestion, are commonly used in food products to give them a buttery or creamy flavoring, and have recently been shown to be present in sweet-flavored ENDS solutions. When inhaled, high doses of these diketones cause acute-onset bronchiolitis obliterans ("popcorn lung"), a severe and irreversible obstructive lung disease. In the only published study to measure diacetyl or 2,3-pentanedione in ENDS flavorings, these compounds were found to be present in 75% of 159 `sweet flavored' ENDS solutions. However, awareness of this problem is virtually absent from the public health and regulatory discussion of the impact of flavorings on ENDS users, and there has been little study of the pulmonary toxicity of flavorings used in ENDS products, although ENDS are designed to create an ultrafine aerosol that penetrates deeply into the lung. We propose to evaluate the respiratory effects associated with use of sweet- flavored ENDS in 60 users (children and emerging adults) of flavored ENDS solutions likely to contain diketones. We hypothesize that concentrations of diketones in sweet-flavored ENDS will predict adverse acute and subacute effects of ENDS on markers of respiratory health. Acute respiratory effects of using flavored ENDS solutions will be evaluated after a regulated, 5 minute `challenge' with each subject's ENDS solution in a laboratory setting, following a one-week run-in period with a standard ENDS solution without flavor (Specific Aim 1a). Subacute (week-long) respiratory effects will be evaluated after one week of flavored ENDS use (Aim 1b). Outcomes will include potential systemic biological markers of lung damage, including serum levels of club cell secreted protein (CCSP), AREG, and IL-8; and markers of airway inflammation [(fractional excretion of nitric oxide (FeNO)], and of functional changes in FEV1 and FVC. In Aim 2, we will estimate each individual's inhaled dose, based on concentrations of diacetyl and 2,3-pentanedione in each subject's solution, volume of solution used, repeated serum cotinine, and innovative use of data from the Smokio "Smart Vaping" ENDS, which uses an automatic system to record timing, number, and intensity of puffs using a chip within the ENDS that synchronizes data collection to the user's smartphone. Aim 3 will examine the diketone dose-response relationship to adverse respiratory health markers. Diacetyl and related diketone flavorings in ENDS are potentially a major public health threat to children because of widespread use and known respiratory toxicity. Assessment of acute and subacute effects is essential to characterizing this hazard, to the design of subsequent studies to investigate chronic effects, and to evaluation of the need for regulatory intervention.

 描述（由申请人提供）：电子尼古丁输送系统 (ENDS) 中使用的液体调味剂是一种基本上未被认识到的潜在呼吸道危害。ENDS 商业用途中有数千种此类调味剂，其中包括很大一部分甜味或奶油味 ENDS 溶液。 （最流行的调味品之一），用于向儿童和新兴成人营销多种二酮化合物（包括二乙酰和 2,3-戊二酮）。它们被“普遍认为是安全的”摄入，通常用于食品中以赋予其黄油或奶油味，并且最近已被证明存在于甜味 ENDS 溶液中，当吸入时，高剂量的这些二酮会导致急性中毒。闭塞性细支气管炎（“爆米花肺”），一种严重且不可逆的阻塞性肺病，这是唯一一项已发表的测量二乙酰或 2,3-戊二酮的研究。在 ENDS 调味剂中，这些化合物被发现存在于 159 种“甜味”ENDS 解决方案中的 75%。然而，在公众健康和关于调味剂对 ENDS 用户影响的监管讨论中，实际上没有意识到这一问题。尽管 ENDS 旨在产生一种能深入肺部的超细气雾剂，但对 ENDS 产品中使用的调味剂的肺部毒性的研究很少。我们建议评估与此相关的呼吸影响。在 60 名可能含有二酮的调味 ENDS 溶液使用者（儿童和新兴成年人）中使用甜味 ENDS 我们发现，甜味 ENDS 中二酮的浓度将预测 ENDS 对呼吸系统健康指标的不利急性和亚急性影响。使用调味 ENDS 溶液的急性呼吸影响将在实验室环境中对每个受试者的 ENDS 溶液进行 5 分钟的规定“挑战”后进行评估，然后使用不含香料的标准 ENDS 溶液的一周磨合期（具体目标 1a）将在使用调味 ENDS 一周后进行评估（目标 1b）。肺损伤，包括俱乐部细胞分泌蛋白 (CCSP)、AREG 和 IL-8 的血清水平以及气道炎症标志物 [(一氧化氮 (FeNO) 排泄分数])在目标 2 中，我们将根据每个受试者溶液中二乙酰和 2,3-戊二酮的浓度、使用的溶液体积、重复的血清可替宁以及创新使用来估计每个人的吸入剂量。来自 Smokio“智能 Vaping”ENDS 的数据，该 ENDS 使用自动系统通过 ENDS 内的芯片同步数据来记录抽吸的时间、数量和强度目标 3 将检查 ENDS 中二乙酰和相关二酮调味剂的剂量-反应关系，因为其广泛使用和已知的急性呼吸道毒性可能对儿童构成重大公共卫生威胁。亚急性效应对于表征这种危害、设计后续研究以调查慢性效应以及评估监管干预的必要性至关重要。