Laboratory based Evaluation of Tobacco Harm Reduction

描述(申请人提供)：唯一被证实的降低吸烟者癌症风险的方法是完全戒烟，但许多吸烟者无法或不愿戒烟。从概念上讲，如果个人能够减少接触烟草烟雾毒物，那么他们患病的风险就会降低。这一概念被称为减少危害，可以通过提供尼古丁替代来源的新战略和烟草产品的帮助来实现。这些被称为潜在减少暴露产品(PREP))。有些预备品类似香烟，但尼古丁替代疗法和无烟烟草也被认为是预备品。过去，各种实验模型被用来评估与烟草相关的癌症风险，但这些模型都不被认为单独能产生足够的结果，需要更好的筛查方法，目前使用了一组模型组合。备考可以进行类似的测试，但到目前为止，还没有对其进行评估。由于PREP将由既往有很大不同烟草使用史的个人使用，测试范例要求评估风险，减少致癌物暴露后的暴露(例如，“反向剂量-反应关系”)。这一点能否成功也还没有得到评估。这项建议将利用一组传统的和新的测试范例，这些范例将，重要的是，我们将纳入使用香烟烟雾冷凝物的暴露，这些冷凝物模拟“人类”的吞吐轮廓，并评估不同尼古丁暴露的影响。这项建议的目标是1)开发必要的工具，以提供所需的客观科学证据，以充分评估Prep在实验室环境中减少危害的能力，以及2)在现有的Prep和新产品上市时使用这些工具来评估它们。体外和体内模型都将以循序渐进的方式使用，常规(Sencar小鼠)和基因工程小鼠都将接受测试。动物模型将使用皮肤涂抹暴露，但肺组织中的DNA加合物也将被评估。这些实验的总体目的是确定使用实验模型测试不同类型备考的可行性。预科研究的计划公告强调了这一问题的重要性，本提案对此做出了回应。

DESCRIPTION (provided by applicant): The only proven way to reduce cancer risk in smokers is complete cessation, but many smokers are unable or unwilling to quit. Conceptually, if individuals could reduce their exposure to tobacco smoke toxicants, then their risk of disease could be lessened. This concept is known as harm reduction, and could be achieved through the aid of new strategies and tobacco products that provide an alternate source of nicotine. These are called potential reduced exposure products (PREPs)). There are PREPs that are cigarette-like, but also nicotine replacement therapy and smokeless tobacco are also considered to be PREPs. In the past, various experimental models have been used to evaluate tobacco-associated cancer risk, but none of these models are considered to produce sufficient results by themselves, better screening methods are needed, and currently a panel of models is used in combination. PREPs can be tested similarly, but to date, this has not been evaluated. Because PREPs will be used by individuals with widely differing prior tobacco use histories, the testing paradigms call for a assessing risks with reduced exposures following a background of carcinogen exposure (e.g., a "reversed dose-response relationship"). Whether this can be done successfully also has not been evaluated. This proposal will make use of a panel of conventional and novel testing paradigms that will, and importantly we will incorporate exposures using cigarette smoke condensates that simulate "human like" puffing profiles, and assess the effects of varying nicotine exposure. The goals of this proposal are 1) to develop the tools necessary to provide the objective scientific evidence required to adequately evaluate the ability of PREPs to reduce harm in the laboratory setting, and 2) to use these tools to evaluate existing PREPs and new products as they come to market. Both in vitro and in vivo models will be used in a stepped approach, and both conventional (SENCAR mice) and genetically engineered mice will be tested. The animal models will use skin painting exposures, but DNA adducts in lung tissues also will be assessed. The overall purpose of these experiments is to determine the feasibility of testing different types PREPs using experimental models. The importance of this issue is highlighted by the Program Announcement for PREP studies, and this proposal is responsive to that.