Development of Standard Guideline Protocol for Rodent Sub-chronic Tobacco Smoke Inhalation Study
Principal Investigator: Jacob McDonald and Lynn Crosby
Funding Mechanism: Research Contract
ID number: HHSF223201510032I
Award Date: 3/2/2016
Historically, methodologies used in rodent inhalation studies have not adequately described toxicological differences between test cigarettes. This study addresses four key issues observed in the tobacco literature. The first issue is the normalization of tobacco smoke emitted from test cigarettes to 150 mg/m3 total particulate matter (TPM). One problem with this approach is that it normalizes the levels of toxic components present as particulates in tobacco smoke, potentially minimizing differences in toxicity that might arise from differences in particulate matter. A second problem with this approach is that it dilutes the smoke from different test cigarettes with different amounts of air, which results in the uneven dilution of the gas vapor phase. Importantly, the smoke mixture resulting from TPM normalization is very different from the smoke mixture to which smokers might be exposed. The second issue is that there are little available data that allow for a direct toxicological comparison between smoke mixtures generated under the ISO and Canadian Intense (CI) smoking regimens. Third, the vast majority of publicly-available data pertaining to cigarette toxicology has been generated using experimental “reference” cigarettes, which differ greatly in composition from the commercial cigarettes that smokers actually consume. Fourth, most available rodent toxicology studies in the tobacco literature do not address systemic toxicity, but rather focus only on respiratory tract endpoints. The goal of this study is to relate critical toxicological endpoints (e.g., no-observed-adverse-effect level [NOAEL], lowest-observed-adverse-effect level [LOAEL], dose-limiting toxicity) to serially diluted whole smoke from a commercial cigarette generated under the ISO and CI machine smoking regimens. In an initial range-finding study, researchers will expose Sprague-Dawley rats to mainstream smoke generated using a commercial cigarette brand following the CI smoke regimen. Researchers will measure various endpoints, including blood carboxyhemoglobin level, to monitor the rats’ health status. After establishing a reasonably high dose as a top dose, researchers will expose the rats to cigarette smoke for one hour per day for thirteen weeks under different serial dilutions of whole smoke generated under the ISO and CI regimens. Researchers will evaluate end-organ toxicity and conduct in vitro assays to identify different aspects of lung disease. The information obtained will provide: (1) the first publicly-available information on the dose-response curve of serially diluted whole smoke without manipulation of the gas-vapor phase in favor of the particulate phase, (2) a toxicological comparison of the smoke mixtures generated under the ISO and CI machine smoking regimens, and (3) the first publicly-available dose-response information using smoke from an actual cigarette consumed by U.S. smokers. This study is not meant to be the beginning of a series of in vivo toxicology studies using commercial cigarettes; rather, it is meant to provide an empirical basis for evaluation of the toxicology data presently available in the tobacco literature.