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）中使用的液体中的香料是一种基本上未被认识到的潜在呼吸危害。在ENDS中有数千种商业用途的这种调味剂，包括大部分甜味或奶油味的ENDS溶液（最受欢迎的调味剂之一），用于向儿童和新兴成人营销。几种二酮化合物（包括二乙酰和2，3-戊二酮），通常被认为是安全的摄入，通常用于食品中，使其具有黄油或奶油风味，最近已被证明存在于甜味ENDS溶液中。当吸入高剂量的二酮时，会引起急性闭塞性细支气管炎（爆米花肺），这是一种严重的不可逆的阻塞性肺病。在唯一发表的测量ENDS调味品中的双乙酰或2，3-戊二酮的研究中，发现这些化合物存在于159种“甜味”ENDS溶液中的75%。然而，在关于调味品对ENDS使用者的影响的公共卫生和监管讨论中，几乎没有对这个问题的认识，并且很少有关于ENDS产品中使用的调味品的肺毒性的研究，尽管ENDS被设计成产生深深渗透到肺中的超细气溶胶。我们建议在60名可能含有二酮的甜味ENDS溶液使用者（儿童和新生儿）中评价与使用甜味ENDS相关的呼吸影响。我们假设甜味ENDS中二酮的浓度将预测ENDS对呼吸健康标志物的急性和亚急性不良影响。在实验室环境中，在使用不含香料的标准ENDS溶液（具体目标1a）进行一周的导入期后，使用每例受试者的ENDS溶液进行5分钟的规定“激发”后，将评价使用调味ENDS溶液的急性呼吸影响。使用调味ENDS一周后，将评价亚急性（一周）呼吸影响（目标1b）。结果将包括肺损伤的潜在全身生物学标志物，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[（一氧化氮排泄分数（FeNO）]和FEV 1和FVC功能变化的标志物。在目标2中，我们将根据每个受试者溶液中双乙酰和2，3-戊二酮的浓度、所用溶液的体积、重复血清可替宁以及Smokio“Smart Vaping”ENDS数据的创新使用来估计每个人的吸入剂量。和抽吸的强度使用ENDS内的芯片，该芯片将数据收集到用户的智能手机。目的3将检查二酮与不良呼吸健康标志物的剂量反应关系。由于广泛使用和已知的呼吸毒性，ENDS中的双乙酰和相关的二酮调味剂可能对儿童构成重大的公共健康威胁。急性和亚急性影响的评估对于确定这一危险的特征、设计随后的研究以调查慢性影响以及评价是否需要管制干预至关重要。