Biomarkers of toxic response to low nicotine cigarette smoke

描述(申请人提供)：对低尼古丁香烟烟雾的毒性反应的生物标志物。在美国，接触烟草烟雾(主流和环境)是导致死亡的主要原因。卷烟烟雾是一种极其复杂的混合物，在主流和侧流(环境)烟雾组分中都含有大量有毒的多环芳烃(PAH)，如苯并[a]芘(B[a]P)和亚硝胺(如4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone)。这激发了一种概念，即减少接触产品(PREP)将提供更安全的替代产品，例如那些尼古丁含量较低的产品。医学研究所表示，减少危害的产品可能是一项可行且合理的公共卫生政策，特别是对那些无法或不愿戒烟的人。然而，有必要对这些准备工作进行认真评估，以确定减少接触有害物质的特征，并确定减少接触与减少对健康的危害之间是否存在联系。一种名为Quest(R)的Prep使用尼古丁水平较低的转基因烟草，为吸烟者提供一种“戒烟戒烟”的手段。吸烟者通常将尼古丁含量较低的说法解读为香烟危害较小。尼古丁是香烟中的主要成瘾剂，之前的研究表明，当吸烟者改用尼古丁含量较低的香烟时，就会发生补偿性吸烟。吸烟者吸更大更频繁的烟，会接触到更多的烟雾和含有多环芳烃和尼古丁亚硝胺的烟雾颗粒。不同商业卷烟品牌的多环芳烃水平各不相同。Quest(R)香烟在现有的三种尼古丁水平中，每一种都含有大量焦油，因此可能含有与普通香烟相似的毒素。因此，它们有可能成为一种会增加危害的产品。现有的香烟烟雾暴露生物标志物主要用于尼古丁暴露(可替宁水平)和多环芳烃暴露的测量，例如分析1-羟基芘和NNK的尿代谢物--(4-甲基亚硝基)-1-(3-吡啶)-1-丁醇(NNAL)-葡萄糖醛酸脂。唯一使用的毒性生物反应生物标记物是用于监测氧化应激的尿异前列腺素，以及分析白细胞中苯并[a]磷衍生的DNA加合物。因此，迫切需要设计和验证一个更全面的有毒生物反应生物标志物小组，可以用来洞察接触传统香烟和那些尼古丁含量减少的香烟(如Quest(R)香烟)之间的差异。这将使人们有可能更有效地解决Quest(R)香烟是否是一种增加危害的产品。我们建议在最近激动人心的新生物标记物研究的基础上，开发体内尿液和呼气冷凝液(EBC)毒性生物反应生物标记物，并验证羟化B[a]P衍生物作为新的暴露生物标记物。我们假设，这些生物标志物小组将使确定减少尼古丁香烟是否减少有毒生物标志物的排泄成为可能。这一假设将在260名吸烟者中进行受试者内开放标签设计的检验，这些吸烟者报告说目前没有兴趣戒烟，但有兴趣在两个特定目标下尝试新的香烟产品。目的1：采用Quest(R)递减设计，确定与普通香烟相比，吸食尼古丁水平逐渐下降的香烟如何调节接触和尿液中有毒生物反应生物标记物的排泄。目的2：使用Quest(R)非递减研究设计，与吸烟普通香烟相比，严格验证吸烟尼古丁水平逐渐下降时所观察到的尿液和EBC暴露以及毒性生物反应生物标志物的变化。与公共健康相关：在美国，暴露在烟草烟雾中是导致死亡的主要原因。香烟烟雾是一种极其复杂的混合物，包括许多有毒和致癌物质。这激发了一种概念，即减少暴露的产品，如那些尼古丁含量较低的产品，可以提供更安全的替代品。吸烟者通常将尼古丁含量较低的说法解读为香烟的危害较小。我们建议建立一种方法来确定减少尼古丁的香烟是否真的比普通香烟更安全。将开发一组生物标志物，以显示吸食低尼古丁香烟是否会对个体产生毒性反应，以及这种毒性反应是否与吸食传统香烟不同。

DESCRIPTION (provided by applicant): Biomarkers of toxic response to low nicotine cigarette smoke. Exposure to tobacco smoke (mainstream and environmental) is a leading cause of death in the US. Cigarette smoke is an extremely complex mixture including numerous toxic polycyclic aromatic hydrocarbons (PAHs) such as benzo[a]pyrene (B[a]P) and nitrosamines such as 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in both the mainstream and sidestream (environmental) smoke fractions. This has stimulated the concept that reduced exposure products (PREPs) such as those with reduced nicotine content will provide a safer alternative. The Institute of Medicine has suggested that products, which reduce harm, may be a feasible and justifiable public health policy, particularly for those who cannot or will not quit smoking. However, careful evaluation of these PREPs is necessary in order to characterize reductions in exposure to harmful substances, and to determine if there is an association between reduced exposure and reduced harm to health. One type of PREP, called Quest(R), uses genetically modified tobacco with lower nicotine levels to provide a means for smokers to "step down to become nicotine-free". Claims of less nicotine are often interpreted by smokers as meaning that the cigarette is less harmful. Nicotine is the primary addictive agent in cigarettes and previous research has shown that compensatory smoking occurs when smokers are switched to lower nicotine cigarettes. By taking larger and more frequent puffs, a smoker is exposed to more smoke and smoke particulates that contain PAHs and nicotine-derived nitrosamines. PAH levels vary among the different commercial cigarette brands. Quest(R) cigarettes contain significant levels of tar at each of the three nicotine levels that are available and so may contain similar amounts of toxins to regular cigarettes. Therefore, they have the potential to be a harm-increasing product. Existing biomarkers of exposure to cigarette smoke have concentrated on measurements of nicotine exposure (cotinine levels), and PAH exposure such as the analysis 1-hydroxypyrene and the urinary metabolite of NNK, (4- methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL)-glucuronide. The only toxic biological response biomarkers that have been used are urinary isoprostanes to monitor oxidative stress, and the analysis of B[a]P-derived DNA adducts in leukocytes. Therefore, there is a compelling need to devise and validate a more comprehensive panel of toxic biological response biomarkers that can be employed to provide insight into the differences between exposure to conventional cigarettes and those that have reduced nicotine content such as the Quest(R) cigarettes. This will make it possible to more effectively address whether the Quest(R) cigarettes are a harm-increasing product. We propose to build on recent exciting new biomarker studies to develop panels of in vivo urinary and exhaled breath condensate (EBC) toxic biological response biomarkers and to validate hydroxylated B[a]P derivatives as new exposure biomarkers. We hypothesize that these biomarker panels will make it possible to determine whether reduced nicotine cigarettes reduce the excretion of toxic biological biomarkers. The hypothesis will be tested in a within- subject, open-label design of 260 smokers who report not currently being interested in quitting, but interested in trying a new cigarette product under two Specific Aims. Aim 1: To determine how smoking cigarettes with progressive decreases in nicotine levels, using a Quest(R) step-down design, modulates excretion of exposure and toxic biological response biomarkers in urine and EBC when compared with normal cigarettes. Aim 2: To rigorously validate the observed changes in urinary and EBC exposure and toxic biological response biomarkers caused by smoking cigarettes with progressive decreases in nicotine levels using the Quest(R) non-step-down study design when compared with smoking normal cigarettes. PUBLIC HEALTH RELEVANCE: Exposure to tobacco smoke is a leading cause of death in the US. Cigarette smoke is an extremely complex mixture including numerous toxic and cancer-causes substances. This has stimulated the concept that reduced exposure products such as those with reduced nicotine content could provide a safer alternative. Smokers often interpret claims of lower nicotine as meaning that the cigarette is less harmful. We propose to establish a method to determine whether reduced nicotine cigarettes are in fact safer than normal cigarettes. A panel of biomarkers will be developed, which will show whether individuals have a toxic response to smoking low nicotine cigarettes and whether the toxic response is different from smoking conventional cigarettes.