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Clearing the Smoke: Assessing the Science Base for Tobacco Harm Reduction
to determine the cytotoxicity and the genotoxicity of the tobacco product to which humans will be exposed. Such tests have recently been reported for a new tobacco-related PREP (Eclipse Expert Panel, 2000). Such a test must include dose-response studies to determine the amount of the exposure material required to cause toxicity. Next, studies should be conducted in vivo in the best animal models available to determine the comparative potency of the PREP versus the standard product in producing: (1) pulmonary inflammation, (2) COPD, (3) cardiovascular disease, (4) reproductive toxicology, and (5) pulmonary neoplasms.
In vitro studies and in vivo animal studies are useful but limited tools in evaluating the toxicity of products that claim to reduce exposure to tobacco toxicants and potentially reduce tobacco-related harm. In vitro studies may allow rapid, low-cost screening for the toxic properties of conventional tobacco products and tobacco-related PREPs, although the relationship between in vitro toxicity and in vivo human response has not been established for most compounds. These assays include cytotoxicity and genotoxicity assays, which are possible screens for the carcinogenic or inflammatory potential of products. In vivo toxicity testing can be developed to supplement in vitro and clinical studies.
Such animal models, if developed, may be useful as a screening assessment of the efficacy of PREPs for reduction of various tobacco-attributable diseases (see Chapters 12–16). The committee concludes that animal models should be used to test for the potential adverse health effects of tobacco smoke or any proposed additives. The A/J mouse model, which is sensitive to induction of lung adenomas, shows promise as an animal model for screening the potential of tobacco products to induce lung tumors (Witschi et al., 2000; Witschi et al., 1999; Witschi et al., 1997a,b). Future studies should validate the model. These studies (Witschi et al., 2000) indicated that removal of single classes of carcinogens, such as nitrosamine or polycyclic aromatic hydrocarbons (PAHs) may not be protective against induction of lung tumors by smoke. Studies also indicate that some animal models show promise for use in studying the development of symptoms similar to those of chronic obstructive pulmonary disease (COPD), the development of cardiovascular disease, adverse effects on the immune system, intrauterine growth retardation, and poor fetal lung maturation from the inhalation of new or existing tobacco products (see Chapter 10).
Testing the general toxicity of smokeless tobacco and evaluating of the potential harm reduction properties of smokeless tobacco (e.g., Swedish snus) use in smokers may greatly benefit from assays for genotoxic and cytotoxic potential and the animal models discussed above.
Details to be considered in determining the specific set of toxicity tests include species and strain of test animal, duration of test, end points of interest, dose-response considerations, biomarkers of dosimetry and