18.1 Assessing the harmfulness of tobacco and tobacco-like products

Last updated: August 2016 

Suggested citation: Greenhalgh, EM, & Scollo, MM 18.1 Assessing the harmfulness of tobacco and tobacco-like products. In Scollo, MM and Winstanley, MH [editors]. Tobacco in Australia: Facts and issues. Melbourne: Cancer Council Victoria; 2016. Available from http://www.tobaccoinaustralia.org.au/chapter-18-harm-reduction/18-1-assessing

Most diseases caused by tobacco take many years to develop. Real-world effectiveness in reducing harm can be assessed with certainty only after several decades have elapsed.  To assess the potential of a product to reduce exposure or harm, reduction in risks to both individuals and populations need to be assessed for all major types of disease, and against an appropriate baseline (i.e., non-smokers, former smokers, current smokers in the context of host susceptibility and previous level of smoke exposure).1 Measuring constituents of tobacco products and tobacco smoke can provide information on the relative risks to health of tobacco, flavours and additives, and can be used to inform product regulations.2 At the individual level, exposure to tobacco can be quantified through biomarker measurements.1 A good deal is known about the toxic and carcinogenic constituents of tobacco products and tobacco smoke, and the mechanisms by which harm is caused to human physiology over many years. Reducing exposure to such constituents, it is argued, should reduce physiological harm; however, so far little is known about the effectiveness of measures designed to regulate toxicants in tobacco products.3 For a detailed discussion of the constituents of tobacco products in Australia, see chapter 12. For a discussion of proposed regulations, see section 18.2.

18.1.1 Constituents of tobacco products

Tobacco constituents include substances that are naturally present in tobacco, while tobacco ingredients are substances that are added to tobacco during the manufacturing process (i.e., flavours and additives).3 Although it is the chemicals in cigarette smoke that are responsible for the harmful health effects of smoking, understanding the constituents of the products themselves (before burning) is also important, including the nature of the additives. There are several hundred additives in cigarettes, many of which affect the flavour and smell, and hence the palatability of the product and its tolerability to both smokers and bystanders. Some are also used to raise the pH of the smoke, which increases nicotine absorption and therefore addictive potential.2 

18.1.2 Constituents of cigarette smoke

Cigarette smoke comprises a highly complex mixture of a vast number of chemicals, many of which are known to be toxic or carcinogenic, and likely many more that have not yet been evaluated. Reducing concentrations of these constituents, which typically have been measured via smoking machines, has been suggested as a method of reducing health risks; however, using these measures to compare the relative harmfulness of cigarettes is problematic. Machine measurement is useful for comparing products and brands under standard conditions, but fails completely in terms of determining actual deliveries to a smoker3 (for a detailed discussion, see 12.2). Proposed regulations in some jurisdictions would mandate lowering of toxicants in cigarette smoke (see 18.2); however these would also depend on machine measurements, albeit using protocols designed to attempt take into account the ways that consumers smoke (see 12.x for further details). Some experts have suggested that validated tobacco carcinogen and toxicant biomarkers may be a possible solution to the shortcomings of machine measurements3 (see 18.1.3). 

18.1.3 Biomarkers

Biomarkers of tobacco exposure measure the effects of tobacco in a person’s body fluids (including exhaled air) or organs.1 Exhaled carbon monoxide (CO) is one of the most commonly used biomarkers to quantitate exposure to tobacco smoke because it does not undergo metabolic activation; however, limitations include that non-tobacco sources of exposure such as vehicle exhaust can affect measurements, and that levels can change following physical activity or with the presence of lung disease. Other widely used biomarkers include blood nicotine level and its metabolite cotinine, with cotinine used more frequently due to its longer half-life.4  A limitation of cotinine is that it measures exposure to nicotine, rather than the main toxins in tobacco and cannot distinguish between someone who is using a clean form of nicotine (e.g. gum or e-cigarette) and someone who is smoking tobacco.

Biomarkers are affected by inter-individual differences in metabolism,4 and it is unlikely that a single biomarker can sufficiently provide all necessary data regarding the effects of tobacco. Rather, a panel of biomarkers that includes biomarkers of exposure, biologically effective dose, and potential harm can provide more comprehensive information. The usefulness of new products in reducing harm should also be tested in people who differ in their susceptibilities (i.e., people who differ in their behaviour, sex, age, genetics, and history of tobacco use).4 

Carcinogen biomarkers provide an objective measure of carcinogen uptake and metabolic activation and detoxification in people who consume or are exposed to tobacco products, and include DNA adducts, protein adducts and urinary metabolites. Some people more efficiently convert carcinogens to DNA adducts, and may therefore be at higher risk for developing cancer. Carcinogen biomarkers are important in establishing carcinogen dose in people who are exposed to tobacco products and in understanding mechanisms of carcinogenesis, and might ultimately be useful in predicting cancer risk.5 For example, a study in 2014 found an association between low levels of the biomarker serum bilirubin and higher risks of lung cancer incidence and mortality in male smokers, suggesting that it is a useful identifier of smokers at higher risk for lung cancer.6

Researchers have validated a specific panel of tobacco carcinogen and toxicant biomarkers, which they propose can be applied to product regulation and cancer prevention. They suggest that first, a panel of target biomarker levels can be set based on studies of their relationship with cancer risk. Next, the product constituent levels that correspond to the target biomarker levels in the panel should be determined. Finally, regulations could be developed based on these determined constituent levels.7

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1. Stratton K, Padma S, Wallace R, and Bondurant S. Clearing the smoke: assessing the science base for tobacco harm reduction. Institute of Medicine, 2001. Available from: http://www.nap.edu/books/0309072824/html/ .

2. Fowles J and Bates M, The chemical constituents in cigarettes and cigarette smoke: priorities for harm reduction. A report to the New Zealand Ministry of Health: Epidemiology and Toxicology Group, ESR: Kenepuru Science Centre; 2000. Available from: http://citeseerx.ist.psu.edu/viewdoc/download?doi= .

3. Hecht SS. Research opportunities related to establishing standards for tobacco products under the Family Smoking Prevention and Tobacco Control Act. Nicotine & Tobacco Research, 2012; 14(1):18–28. Available from: http://ntr.oxfordjournals.org/content/14/1/18.short

4. Shields PG. Tobacco smoking, harm reduction, and biomarkers. Journal of the National Cancer Institute, 2002; 94(19):1435–44. Available from: http://jnci.oxfordjournals.org/content/94/19/1435.long#ref-38

5. Hecht SS. Tobacco carcinogens, their biomarkers and tobacco-induced cancer. Nature Reviews Cancer, 2003; 3(10):733–44. Available from: http://www.nature.com/nrc/journal/v3/n10/full/nrc1190.html

6. Wen C-P, Zhang F, Liang D, Wen C, Gu J, et al. The ability of bilirubin in identifying smokers with higher risk of lung cancer: a large cohort study in conjunction with global metabolomic profiling. Clinical Cancer Research, 2015; 21(1):193–200. Available from: http://www.ncbi.nlm.nih.gov/pubmed/25336700

7. Hecht SS, Yuan J-M, and Hatsukami D. Applying tobacco carcinogen and toxicant biomarkers in product regulation and cancer prevention. Chemical Research in Toxicology, 2010; 23(6):1001–8. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2891118/