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The difficulties encountered in extrapolating biological activity from cigarette smoke composition provide generally applicable lessons as they are representative of the problems encountered with other complex mixtures. Researchers attempting to assess risk are faced with attempting to interpret data from a number of areas including: tobacco science; smoke/aerosol chemistry specific to tobacco; sophisticated analytical chemistry applications and techniques for trapping, collecting, separating, and quantifying very specific compounds at nanogram to picogram levels; numerous biological testing methodologies; and animal models of tumors and carcinogenesis. Numerous hypotheses have been developed over the past five decades and tested with the technology of the day in attempts to interpret the biological activity of cigarette smoke in relation to the chemistry of this complex mixture. These hypotheses fall into several categories discussed in this review: mechanisms of pyrogenesis of polycyclic aromatic hydrocarbons (PAHs) in tobacco smoke; levels of PAHs in cigarette mainstream smoke (MS) and its tumorigenicity in mouse skin-painting experiments; control of PAH levels in MS; chemical indicators of cigarette smoke condensate (CSC) tumorigenicity; control of levels of MS components partitioned between the vapor phase and particulate phase of MS; tumorigenic threshold limits of CSC and many of its components; tumorigenic aza-arenes in tobacco smoke; MS components reported to be ciliastatic to smokers' respiratory tract cilia; anticarcinogenic tobacco-smoke components. Of 52 hypotheses reviewed in this paper, 15 have excellent data supporting the hypothesis based on today's technology. The remaining 37 hypotheses, although originally plausible, have since become insupportable in light of new and contradictory data generated over the years. Such data were generated sometimes by the original authors of the hypotheses and sometimes by other investigators. The hypotheses presented today are less likely to be supplanted because they are well conceived and have a strong mechanistic basis. The challenge for the future is the generation and interpretation of data relating the chemistry and biological activity associated with the dynamic and complex mixture of tobacco smoke.

Tobacco and tobacco smoke are both complex mixtures. We previously reported 8430 unique chemical components identified in these complex mixtures but two years later our updated number was 8889. Addition of unlisted isomers raised these numbers to 8622 and 9081, respectively. Our previous number of 4994 identified tobacco components is now 5229; our previous number of 5315 identified tobacco smoke components is now 5685. An operational definition of a complex mixture is as follows: A complex mixture is a characterizable substance containing many chemical components (perhaps thousands) in inexact proportions.Detailed knowledge of the amount and type of each component within the substance is uncertain even with today's analytical technology. Although it has been estimated that as many as 100000 components are present in these complex mixtures, their analyses indicate that the vast majority of the mass of each of these complex mixtures accounts for the 8430 compounds reported previously. Over 98.7% of the mass of tobacco has been accounted for in terms of identified components in tobacco. Greater than 99% of the mass of whole smoke has been accounted for based on identified chemical components. Certainly, many more tobacco and tobacco smoke components are present in these complex mixtures but the total mass of these components obviously is quite small.One of the significant challenges we face as a scientific community is addressing the problems of determining the risk potential of complex mixtures. Many issues are associated with toxicological testing of the complex mixture of tobacco smoke. Conducting valid experiments and interpreting the results of those experiments can be quite difficult. Not only is the test agent a complex mixture but also the tests are performed on species that have complicated life-processes. Interpretations of test results are often paradoxical. Significant progress has been made in the toxicological evaluations of complex mixtures in the last 80 years. The challenges we face in terms of testing the biological properties of tobacco smoke are substantial. The statement by DIPPLE et al. in their summary of the research on polycyclic aromatic hydrocarbons from the 1930s through 1980 is equally true today for the cigarette smoke situation:…many important questions remain unanswered…many questions persist despite the considerable progress that has been made.