Biomarkers of toxic response to low nicotine cigarette smoke

描述（由申请方提供）：对低尼古丁香烟烟雾产生毒性反应的生物标志物。暴露于烟草烟雾（主流和环境）是美国死亡的主要原因。香烟烟雾是一种极其复杂的混合物，在主流和侧流（环境）烟雾组分中包括许多有毒的多环芳烃（PAH）如苯并[a]芘（B[a]P）和亚硝胺如4-（甲基亚硝胺基）-1-（3-吡啶基）-1-丁酮（NNK）。这激发了减少暴露产品（PREP）的概念，例如尼古丁含量降低的产品将提供更安全的替代品。医学研究所建议，减少危害的产品可能是一种可行和合理的公共卫生政策，特别是对于那些不能或不愿戒烟的人。然而，为了描述有害物质暴露减少的特征，并确定暴露减少与健康危害减少之间是否存在关联，有必要对这些PREP进行仔细评估。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”的方法。尼古丁含量较低的说法通常被吸烟者解释为意味着香烟的危害较小。尼古丁是香烟中的主要成瘾剂，先前的研究表明，当吸烟者转向尼古丁含量较低的香烟时，会发生补偿性吸烟。通过更大和更频繁的吸烟，吸烟者暴露于更多的烟雾和含有多环芳烃和尼古丁衍生的亚硝胺的烟雾颗粒。PAH水平因不同的商业香烟品牌而异。Quest（R）香烟在三种尼古丁水平中的每一种都含有大量的焦油，因此可能含有与普通香烟相似的毒素。因此，它们有可能成为增加危害的产品。暴露于香烟烟雾的现有生物标志物集中在尼古丁暴露（可替宁水平）和PAH暴露的测量上，例如分析1-羟基芘和NNK的尿液代谢产物（4-甲基亚硝胺基）-1-（3-吡啶基）-1-丁醇（NNAL）-葡糖苷酸。已使用的唯一毒性生物反应生物标志物是监测氧化应激的尿异前列腺素，以及白细胞中B[a] P衍生DNA加合物的分析。因此，迫切需要设计和验证一组更全面的毒性生物反应生物标志物，该生物标志物可用于提供对暴露于常规香烟和具有降低的尼古丁含量的香烟（如Quest香烟）之间的差异的了解。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。我们建议建立在最近令人兴奋的新的生物标志物的研究，在体内尿液和呼出气冷凝液（EBC）的毒性生物反应的生物标志物，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的香烟是否会减少有毒生物标志物的排泄。该假设将在260名吸烟者的受试者内、开放标签设计中进行检验，这些吸烟者报告目前对戒烟不感兴趣，但有兴趣在两个特定目的下尝试新的卷烟产品。目标1：为了确定与正常香烟相比，使用Quest（R）逐步下降设计吸烟如何调节尿液和EBC中暴露和毒性生物反应生物标志物的排泄。目标二：采用Quest（R）非递减研究设计，与吸烟正常香烟相比，严格验证吸烟引起的尿液和EBC暴露以及毒性生物学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，暴露于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。这激发了一种概念，即减少暴露的产品，如尼古丁含量减少的产品，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释为香烟的危害较小。我们建议建立一种方法，以确定是否减少尼古丁香烟实际上比正常香烟更安全。一组生物标志物将被开发出来，这将显示个体是否对吸烟低尼古丁香烟产生毒性反应，以及这种毒性反应是否与吸烟传统香烟不同。

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.