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法规研究小组（TobReg）建议强制减少香烟烟雾中的选定致癌物和有毒物，根据《家庭吸烟预防和烟草控制法》，美国现在可以这样做。虽然强制减少个别有毒物质和致癌物质可能不一定会导致健康风险的减少，但通过改变卷烟制造方法，可以大大减少卷烟烟雾中的一些强致癌物质。因此，总体目标将是逐步降低主流烟气中这些成分的水平，如通过标准化机器确定的方法所测量的。然而，如何测试和调节香烟烟雾的含量是一个关键的挑战。目前使用的标准机器测试方法没有考虑到吸烟者-香烟相互作用的复杂性，并且被广泛认为不足以预测人体暴露。TobReg研究小组建议确定每毫克尼古丁的有毒物质水平。然而，目前尚不清楚香烟烟雾中每毫克尼古丁排放量的成分与吸烟者个体成分暴露量有何关系，以及哪些因素可能影响这种关系。此外，目前尚不清楚传统使用的标准吸烟机方案中的哪一种可以在美国香烟中提供与吸烟者的暴露最密切相关的每mg尼古丁水平的成分。我们提案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，我们将重点关注致癌烟草特有的亚硝胺N2-亚硝基去甲烟碱（NNN）和4-亚硝基去甲烟碱。（甲基亚硝胺）-1-（3-吡啶基）-1-丁酮（NNK）进行研究，具体目标如下：（1）研究在不同吸烟方案下，各种美国香烟品牌每毫克尼古丁的NNN和NNK排放量。(2)检查NNN和NNK/mg尼古丁含量的变化在多大程度上成功预测了吸烟者暴露于这些致癌物的变化。(3)确定哪些个体因素（例如，吸烟持续时间和强度、尼古丁代谢、人口统计学）可能影响机器测量的TSNA/mg尼古丁与吸烟者暴露量之间的关系。出于监管目的，在检查成分/mg尼古丁烟雾量时，可能需要考虑这些因素。这项研究对于扩大FDA制定、评估和实施烟草产品法规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.