Biomarkers of toxic response to low nicotine cigarette smoke

描述（由申请人提供）：低尼古丁香烟烟雾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，包括许多有毒的多环芳烃（PAHs），如苯并[a]芘（B[a]P）和亚硝胺，如4-（甲基亚硝胺）-1-（3-吡啶基）-1-丁酮（NNK），在主流和侧流（环境）烟雾组分中都有。这激发了人们的观念，即尼古丁含量降低的低暴露产品（PREPs）将是一种更安全的替代品。医学研究所建议，减少伤害的产品可能是一项可行和合理的公共卫生政策，特别是对那些不能或不愿戒烟的人。然而，有必要对这些预准备物质进行仔细评估，以确定有害物质接触减少的特征，并确定接触减少与对健康的危害减少之间是否存在关联。一种名为Quest(R)的PREP使用尼古丁含量较低的转基因烟草，为吸烟者提供一种“戒烟戒烟”的手段。吸烟者常常把尼古丁含量更低的说法解读为香烟的危害更小。尼古丁是香烟中的主要成瘾性物质，以前的研究表明，当吸烟者转向尼古丁含量较低的香烟时，就会出现代偿性吸烟。通过更大、更频繁地吸烟，吸烟者暴露在更多的烟雾和含有多环芳烃和尼古丁衍生亚硝胺的烟雾颗粒中。不同商业香烟品牌的多环芳烃含量各不相同。Quest(R)香烟在三种尼古丁水平中都含有大量的焦油，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增加危害的产品。现有的暴露于香烟烟雾的生物标志物集中在尼古丁暴露（可替宁水平）和多环芳烃暴露的测量上，如分析1-羟基芘和尿中NNK代谢物（4-甲基亚硝胺）-1-（3-吡啶基）-1-丁醇(NNAL)-葡萄糖醛酸。目前使用的唯一毒性生物反应生物标志物是尿异前列腺素，用于监测氧化应激，以及白细胞中B[a] p来源的DNA加合物的分析。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，可以用来深入了解接触传统香烟和那些尼古丁含量较低的香烟（如Quest(R)香烟）之间的差异。这将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。我们建议以最近令人兴奋的新生物标志物研究为基础，开发体内尿液和呼出冷凝水（EBC）毒性生物反应生物标志物，并验证羟基化B[a]P衍生物作为新的暴露生物标志物。我们假设，这些生物标志物小组将有可能确定减少尼古丁香烟是否减少有毒生物标志物的排泄。这一假设将在260名吸烟者的实验对象内进行测试，这些吸烟者目前对戒烟不感兴趣，但有兴趣在两个特定目标下尝试一种新的香烟产品。目的1：使用Quest(R)降压设计，确定与正常香烟相比，吸烟尼古丁水平逐渐降低，如何调节尿和EBC中暴露的排泄和毒性生物反应生物标志物。目的2：与吸烟正常香烟相比，使用Quest(R)非降压研究设计严格验证吸烟引起的尿液和EBC暴露和毒性生物反应生物标志物的观察变化，尼古丁水平逐渐降低。公共卫生相关性：在美国，接触烟草烟雾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。这激发了一种观念，即减少尼古丁含量的产品可以提供更安全的替代品。吸烟者常常把尼古丁含量较低的说法理解为香烟的危害较小。我们建议建立一种方法来确定低尼古丁香烟是否真的比普通香烟更安全。一个生物标志物小组将被开发出来，它将显示个人是否对吸低尼古丁香烟有毒性反应，以及这种毒性反应是否与吸传统香烟不同。

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.