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

 描述(由申请人提供)：电子尼古丁输送系统(END)中使用的液体中的调味料是一种在很大程度上未被认识到的潜在呼吸危害。在商业用途中，Ends有数千种这样的口味，包括很大比例的甜味或奶油味Ends解决方案(最受欢迎的调味品之一)，用于向儿童和新兴成年人营销。几种双酮类化合物(包括双乙酰和2，3-戊二酮)被“普遍认为是安全的”可以摄入，它们通常用于食品中，以增加黄油或奶油的味道，最近已被证明存在于甜味的末端解决方案中。当吸入这些二酮时，会导致急性闭塞性毛细支气管炎(“爆米花肺”)，这是一种严重的不可逆转的阻塞性肺部疾病。在唯一发表的一项测量末端调味品中双乙酰或2，3-戊二酮的研究中，发现在159种甜味末端溶液中75%存在这些化合物。然而，在公共卫生和监管机构对调味品对最终用户影响的讨论中，几乎没有意识到这个问题，而且几乎没有关于最终产品中使用的调味品的肺部毒性的研究，尽管END旨在创建一种深入肺部的超细气雾剂。我们建议在60名可能含有二酮的调味末端溶液的使用者(儿童和初出茅庐的成年人)中评估与使用甜味末端相关的呼吸影响。我们假设甜味末端中的二酮浓度将预测末端对呼吸健康标志物的不良、急性和亚急性影响。使用有风味的END溶液的急性呼吸影响将在实验室环境中对每个受试者的END溶液进行5分钟的规定的“挑战”后进行评估，在与无香料的标准END溶液进行一周的磨合期之后(具体目标1a)。亚急性(长达一周)的呼吸影响将在香料末端使用一周后评估(目标1b)。结果将包括潜在的肺损伤的全身生物标志物，包括血清俱乐部细胞分泌蛋白(CCSP)、AREG和IL-8的水平；以及呼吸道炎症的标志物[一氧化氮(FeNO)的排泄分数]，以及FEV1和FVC的功能变化。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、溶液使用量、重复的血清可替宁以及Smokio智能吸管末端的数据的创新使用来估计每个人的吸入剂量，该末端使用一个自动系统来记录喷雾的时间、数量和强度，该芯片使用末端内的芯片将数据收集同步到用户的智能手机。目的3将检查二酮与不良呼吸道健康标志物的剂量-反应关系。由于广泛使用和已知的呼吸道毒性，末端的双乙酰和相关的双酮调味料可能对儿童的公共健康构成重大威胁。对急性和亚急性影响的评估对于确定这一危险的特征、设计后续研究以调查慢性影响以及评估监管干预的必要性至关重要。

 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.