the standard product. Any new material, such as flavors, added to standard products must be included in the analyses. It is important to analyze the product that actually enters the body (for example, the combustion products that are inhaled) rather than the composition of the product as sold.

The approach to testing the toxicity of the material to which people are exposed in the tobacco-related PREP compared to standard tobacco products is discussed in Chapter 10. The objectives of the toxicity tests are to determine what toxic effects can be induced by the test materials (the tobacco-related PREP compared to the standard product) and how much of the test materials is required to cause the adverse effect, i.e., the dose-response characteristics in animals of the test materials. Data from animal studies can be used to eliminate new products that are much more toxic than existing ones.

A series of comparative potency tests is appropriate. In vitro studies in cultured cells from both animals and humans can be used to determine the ability of the test materials (from the tobacco-related PREP and the standard product) to induce cellular damage, an inflammatory response, or cell death. Assays of the mutagenic or clastogenic activity of the test materials can be done in bacterial or mammalian cell systems.

In animal studies, tests for tobacco-related toxicity should include evaluation of the ability to induce adverse health effects or cancer in the respiratory tract, the nervous system, the cardiovascular system, the reproductive and developmental systems, and other organs. Toxicokinetic studies should be used to determine dosimetry to different organs and to suggest biomarkers of internal dose that can be used in humans. Short-term clinical tests in humans should be done to compare the potencies of the test materials to induce acute adverse health effects (such as reduced pulmonary function) and to determine the toxicokinetics of the tobacco-related PREP compared to the standard product.

For dose-response assessment, the questions include:

  • What are the dose-response characteristics of the PREP compared to the conventional tobacco product?

  • Do smokers use PREPs at a time in their individual smoking history (and therefore of disease progression) that induce different dose-response effects?

  • Are the patterns of adverse health effects different from PREPs compared to conventional tobacco products?

  • What is the evidence that reduction in exposure to the targeted compounds in the complex mixture or other hazardous material in the PREP will decrease or reverse the development of disease?

  • What is the dose-response relationship between the targeted compounds and the disease outcome?

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