Oxidant Exposure and Related Harm from Tobacco Smoke

摘要 吸烟的毒性和对健康的负面影响是由于吸入了一种复杂的混合物， 7000种化学物质，包括许多有毒物质和致癌物质，被列入FDA的有害和潜在危险清单。 有害成分（HPHCs）。氧化剂是烟草烟雾中富含的主要类别的有毒物质， 被认为在烟草相关疾病的发展中起关键作用，包括COPD、CVD和癌症 通过氧化应激/损伤和炎症的产生。然而，特定的氧化剂大多数 责任人仍不清楚。虽然有几种氧化剂被列入HPHC名单（如。羰基化合物）， 大多数反应性的、破坏性的和丰富的种类，自由基，没有被表示。最近我们发现， 不同香烟品牌的自由基传递差异很大（>12倍），受产品的影响很大 设计（例如烟草品种）和吸烟行为，在其他流行的可燃产品中也很高 包括过滤雪茄自由基的传递也与其他氧化剂包括羰基化合物高度相关 （例如：丙烯醛）。基于这些发现，我们提出烟草衍生的氧化剂，包括自由基， 是制定监管战略的一个重要目标，旨在减少 使用可燃烟草。我们的初步研究结果有力地支持了这种方法， 氧化应激生物标志物在从高氧化剂转换为低氧化剂的吸烟者中显著降低 香烟该项目的目标是确定特定的氧化剂负责生成的 烟草相关的危害，并确定氧化剂还原对烟草相关毒性终点的影响。到 为此，我们提出了三个具体目标。在目标1中，我们将确定自由基的水平和身份， 不同可燃烟草产品/品牌使用先进电子技术输送的其他氧化剂 顺磁共振（EPR）光谱和液相色谱-串联质谱（LC-MS） MS/MS）方法。在目标2中，我们在相关小鼠模型中进行了暴露研究，以确定 烟草烟雾氧化剂对肺损伤和炎症的影响;比较高氧化剂与低氧化剂的影响 品牌和烟草品种。在目标3中，我们将进行小鼠暴露研究，以确定 活性炭过滤香烟烟雾对小鼠氧化性肺损伤的影响。总的来说，这些研究将 通过关注烟草的毒理学重要性，为烟草监管科学领域做出重大贡献。 氧化剂暴露。这些数据对于FDA制定监管政策具有特别的价值 旨在减少烟草使用带来的危害。

Abstract Toxicity and negative health effects of tobacco smoking results from the inhalation of a complex mixture of over 7000 chemicals including many toxicants and carcinogens included on the FDA list of Harmful and Potentially Harmful Constituents (HPHCs). Oxidants are a major class of toxicant abundant in tobacco smoke and are thought to play a critical role in the development of tobacco related diseases including COPD, CVD and cancer through the generation of oxidative stress/damage and inflammation. However, the specific oxidants most responsible remain unclear. While several oxidants are included on the HPHC list (eg. carbonyls), one of the most reactive, damaging and abundant classes, free radicals, are not represented. Recently we found that delivery of radicals varied greatly (>12-fold) across cigarette brands, was substantially impacted by product design (e.g. tobacco variety) and smoking behaviors and was high in other popular combustible products including little filtered cigars. Radical delivery was also highly correlated with other oxidants including carbonyls (eg. acrolein). Based upon these findings, we propose that tobacco-derived oxidants, including free radicals, represent an important target for developing regulatory strategies aimed at reducing the harm from combustible tobacco use. This approach is strongly supported by our preliminary findings that levels of oxidative stress biomarkers are significantly reduced in smokers who switch from high to low oxidant cigarettes. The objectives of this project are to identify specific oxidants responsible for the generation of tobacco related harm and determine the impact of oxidant reduction on tobacco-related toxicity endpoints. To this end, we propose 3 specific aims. In Aim 1, we will determine the levels and identity of free radicals and other oxidants delivered by different combustible tobacco products/brands using advanced electron paramagnetic resonance (EPR) spectroscopy and liquid chromatography-tandem mass spectrometry (LC- MS/MS) methodologies. In Aim 2 we conduct exposure studies in a relevant mouse model to determine the impact of tobacco smoke oxidants on lung damage and inflammation; comparing effects of high vs. low oxidant brands and tobacco varieties. In Aim 3, we will conduct mouse exposure studies to determine the impact of charcoal filtration of cigarette smoke on oxidant-induced lung damage in the mouse. Overall, these studies will significantly contribute to the field of tobacco regulatory science by focusing on the toxicological importance of oxidant exposure. These data will be of particular value to the FDA for the development of regulatory policies aimed at reducing harm imposed by tobacco usage.