This report has not reviewed potential cancer risks due to fibers released from cigarette filters or tobacco additives, because it is thought that the risk of these exposures are substantially lower than the risk from the constituents of tobacco smoke. However, there are no existing data to prove this assumption. Importantly, as harm reduction products are developed that substantially reduce exposure to tobacco constituents, the relative role of fibers and additives in carcinogenesis might become more important. Thus, fiber and additive exposure should be considered when assessing PREPs.

Utility in a Preclinical Setting

There are some experimental models (e.g., in vitro cell cultures, laboratory animals) that may be useful for the assessment of the carcinogenicity of tobacco-related PREPs. Although there are many reasonable models with which to assess individual tobacco smoke products, better models are needed for assessing exposures to complex mixtures. Such studies are not alone sufficient to support claims of potential harm reduction. No claim of potential harm reduction should be allowed without adequate human clinical and epidemiological studies. In vitro and animal studies, however, are very important for (1) determining those products that are not likely to result in measurable harm reduction (e.g., if the product results in exposures that increase genotoxicity, then there would be less enthusiasm for it and so should not be tested in a human clinical study and should not be introduced into the marketplace); (2) identifying unforeseen reactions (e.g., if a product reduces exposure but does not decrease tumors), then there might be some constituent or combination of constituents that is either new or more important than those changed in the product); (3) providing supportive evidence for the use of a particular bioassay in humans (e.g., if a biomarker predicts cancer risk in experimental animals); and 4) assessing the dose-response and the shape of the regression of risk for the PREP as exposure is reduced, although the data should be considered qualitative or semiquantitative and cannot be extrapolated directly to human smoking risk. Both in vitro cell culture and experimental animal studies should be used in assessing PREPs, where both can assess genotoxic and nongenotoxic end points, and chronic animal bioassays are needed to assess the end point of cancer risk. It is beyond the scope of the committee to recommend the specific panel of assays, but such a panel will need to be developed. Also, these studies should assess changes due to both specific carcinogens and to complex mixtures, where the latter should be mandatory.

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