Constituent yields and biomarkers of exposure for tobacco product regulation

描述(由申请人提供)：世界卫生组织烟草产品监管研究小组(Tobreg)建议强制减少部分致癌物质和有毒物质的香烟烟雾，目前根据《家庭吸烟预防和烟草控制法案》在美国是可能的。虽然强制减少个别毒物和致癌物不一定会降低健康风险，但通过改进卷烟制造方法，卷烟烟雾中的一些潜在致癌物可以大幅减少。因此，总体目标将是逐步降低通过标准化机器确定的方法测量的主流烟雾中的这些成分的水平。然而，如何测试和监管香烟烟雾含量的问题是一个严峻的挑战。目前使用的标准机器测试方法没有考虑到吸烟者与香烟相互作用的复杂性，并且被广泛认为不足以预测人体接触。TobReg研究小组建议确定每毫克尼古丁的毒物水平。然而，目前还不知道香烟烟雾中每毫克尼古丁的成分排放量如何与吸烟者接触的各个成分有关，以及哪些因素可能影响这种关系。此外，还不清楚哪种传统使用的标准吸烟机疗法可能会在美国香烟中提供与吸烟者暴露最密切相关的每毫克尼古丁成分水平。我们提议的目标是解决这些关键差距。基于我们在烟草产品和暴露生物标志物分析方面的专业知识，我们将专注于致癌烟草特有的亚硝胺N-亚硝胺(NNN)和亚硝胺(4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone)，以进行以下具体目标的研究：(1)检测不同吸烟方式下不同美国卷烟品牌每毫克尼古丁的NNN和NNK值。(2)研究烟雾中每毫克尼古丁产量的NNN和NNK的变化在多大程度上能成功预测吸烟者接触这些致癌物的变化。(3)确定哪些个人因素(如吸烟时间和强度、尼古丁代谢、人口统计学)可能影响机器测量的每毫克尼古丁的TSNA与吸烟者暴露之间的关系。出于监管目的，在检查成分/毫克尼古丁烟产量时，可能需要考虑这些因素。这项研究对于扩大为FDA制定、评估和实施烟草产品法规提供信息的科学基础至关重要。

DESCRIPTION (provided by applicant): A mandated reduction in cigarette smoke of selected carcinogens and toxicants has been recommended by the World Health Organization Study Group on Tobacco Product Regulation (TobReg) and is now possible in the U.S. under the Family Smoking Prevention and Tobacco Control Act. Although a mandated reduction of individual toxicants and carcinogens may not necessarily lead to reduction in health risks, some potent carcinogens in cigarette smoke can be substantially reduced by modifying cigarette manufacturing approaches. Therefore, the overall goal would be to progressively reduce levels of these constituents in mainstream smoke as measured by standardized machine determined methods. However, the issue of how to test and regulate the contents of cigarette smoke represents a critical challenge. The currently used standard machine testing methods do not account for the complexities of smoker-cigarette interaction and are widely recognized to be inadequate for the prediction of human exposures. TobReg study group recommended that levels of toxicants be established per mg of nicotine. However, it is not known how the constituent per mg nicotine emissions in cigarette smoke are related to individual constituent exposures in smokers, and which factors may affect this relationship. Moreover, it is not clear which of the traditionally used standard smoking machine regimens may deliver constituent per mg nicotine levels in the U.S. cigarettes that are most closely related to the smokers' exposure. The goal of our proposal is to address these critical gaps. Building on our expertise in the analysis of tobacco products and biomarkers of exposure, we will focus on the carcinogenic tobacco-specific nitrosamines N2-nitrosonornicotine (NNN) and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) to conduct research as described in the following specific aims: (1) To examine NNN and NNK per mg nicotine emissions in various U.S. cigarette brands under different smoking regimens. (2) To examine the extent to which changes in NNN and NNK per mg nicotine yields in smoke succeed in predicting changes in smokers' exposure to these carcinogens. (3) To determine which individual factors (for example, duration and intensity of smoking, nicotine metabolism, demographics) may affect the relationship between the machine- measured TSNA per mg nicotine and exposures in smokers. These factors may need to be considered when examining constituent/mg nicotine smoke yields for regulatory purposes. This research is critical for expanding the science base that informs the FDA as it develops, evaluates, and implements tobacco product regulations.