Laboratory based Evaluation of Tobacco Harm Reduction

描述（由申请人提供）：降低吸烟者癌症风险的唯一行之有效的方法是完全戒烟，但许多吸烟者无法或不愿意戒烟。从概念上讲，如果个人能够减少接触烟草烟雾有毒物质，那么他们患病的风险就可以降低。这一概念被称为减少危害，可以通过新的策略和烟草产品提供尼古丁的替代来源来实现。这些被称为潜在的减少暴露产品（PREP）。有类似尼古丁的PREP，但尼古丁替代疗法和无烟烟草也被认为是PREP。在过去，各种实验模型已被用于评估烟草相关癌症风险，但这些模型都被认为不能单独产生足够的结果，需要更好的筛选方法，目前一组模型被组合使用。PREP可以进行类似的测试，但迄今为止，这还没有得到评估。由于PREP将由具有广泛不同的先前烟草使用史的个体使用，因此测试范例要求在致癌物暴露背景（例如，“反向剂量-反应关系”）。这是否能成功地做到，也没有得到评估。该提案将利用一组传统和新型测试范例，重要的是，我们将使用模拟“人类”抽吸特征的香烟烟雾冷凝物进行暴露，并评估不同尼古丁暴露的影响。本提案的目标是：1）开发必要的工具，以提供充分评价PREP在实验室环境中减少伤害的能力所需的客观科学证据; 2）使用这些工具评价现有PREP和上市的新产品。体外和体内模型都将以分步方法使用，并将测试常规（SENCAR小鼠）和基因工程小鼠。动物模型将使用皮肤绘画暴露，但也将评估肺组织中的DNA加合物。这些实验的总体目的是确定使用实验模型测试不同类型PREP的可行性。PREP研究的计划公告强调了这一问题的重要性，本提案就是对这一问题的回应。

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.