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Maciej L. Goniewicz
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ES11 - Lung Cancer Plasticity and Drug Resistance (ID 14)
- Event: WCLC 2019
- Type: Educational Session
- Track: Biology
- Presentations: 1
- Now Available
- Moderators:Luca Roz, Nagahiro Saijo
- Coordinates: 9/08/2019, 15:15 - 16:45, Colorado Springs (1994)
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ES11.06 - Toxicology of Tobacco and Metabolites, and Impact on Cancer (Now Available) (ID 3216)
15:15 - 16:45 | Presenting Author(s): Maciej L. Goniewicz
- Abstract
- Presentation
Abstract
Tobacco smoke is a significant source of exposure to toxic compounds among active smokers and those exposed to secondhand smoke (SHS). Over 7000 chemicals have been identified in tobacco smoke, including 69 known carcinogens. Characterizing human exposure to tobacco smoke constituents is important for public health efforts aimed at reducing exposure to these chemicals. Tobacco smoke exposure can be assessed through biomonitoring, i.e., by measuring the concentration of a toxicant or its metabolites in human physiological fluids. Biomarkers, ideally unique to a toxic mixture such as tobacco smoke, are useful for exposure assessment and for source apportionment. Nicotine, its metabolites, and the tobacco-specific nitrosamine (TSNA) metabolite 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) are the most specific of the commonly used biomarkers for tobacco smoke exposure. Carbon monoxide, metabolites of volatile organic compounds (VOCs), and polycyclic aromatic hydrocarbons (PAHs) metabolites, are also useful biomarkers, but they have sources other than tobacco smoke. Levels of these biomarkers are generally elevated in smokers as compared to nonsmokers, but specificity may be inadequate to measure SHS exposure. In general, biomarker studies can demonstrate internal exposure to toxic constituents due to tobacco product use and can be used to assess relative harm of modified-risk tobacco products. Epidemiologic studies directly support a link between exposure to tobacco-specific toxicants and subsequent risk for cancer in smokers of conventional cigarettes as well as lifelong never-smokers.
Nicotine metabolites and total nicotine equivalents (sum of nicotine, cotinine, 3ʹ-hydroxycotinine, and their glucuronides), which can be measured in urine, blood or saliva, represent approximately 73%–96% of the nicotine dose and provide a superb indicator of nicotine uptake. Although nicotine was one of the first biomarkers to be used for assessing exposure to cigarette smoke, its short half-life (t1/2=~2 h) and variable rate of metabolism led to the use of cotinine and other nicotine metabolites as biomarkers of nicotine exposure. Cotinine is the major metabolite of nicotine, and its longer elimination half-time (t1/2=16–18 h) makes it a good biomarker for nicotine uptake in various biological fluids and tissues. The nicotine metabolite ratio (ratio of 3ʹ-hydroxycotinine to cotinine) in plasma is an excellent phenotypic indicator of hepatic CYP2A6 activity in smokers and can be used as a measure of individual risk for addiction.
Tobacco-specific nitrosamines (TSNAs) include the potent lung carcinogen NNK and the oral cavity and esophageal carcinogen N′-nitrosonornicotine (NNN) and are—as indicated by their common name—regarded as completely specific to tobacco. Consequently, these compounds and their metabolites are among the most important biomarkers for monitoring tobacco exposure and evaluating cancer risk in tobacco users. NNAL is a metabolite of NNK and itself is a carcinogen. A key benefit of NNAL assays is the compound’s elimination half-time ( t1/2 of 10–18 days), which is longer than other tobacco biomarkers. The main disadvantage is that the urinary concentration of NNAL is many times lower than that of cotinine, so the assay is more technically challenging and expensive to perform. Measurements of NNAL typically require extensive sample preparation and fewer laboratories can reliably measure NNAL than cotinine or nicotine.
Polycyclic aromatic hydrocarbons (PAHs) are ubiquitous environmental pollutants formed from incomplete combustion of organic matter and use of combustible tobacco products results in substantial exposure to those chemicals. Over 500 PAHs and their alkyl derivatives have been identified in tobacco smoke. Some PAHs induce tumors in animals and are carcinogenic to humans. For example, benzo[a]pyrene induces malignant lesions in animal studies. Urinary concentrations of PAH metabolites, specifically monohydroxylated PAHs, have been used as biomarkers of human exposure to PAHs including naphthalene, fluorene, phenanthrene and pyrene. The PAH exposure profiles for tobacco smoke may differ from other sources, and it may be possible to identify PAH biomarkers that are more selective for tobacco smoke than others.
Volatile organic compounds (VOCs) are a diverse group of chemicals that are abundant in tobacco product emissions and in the polluted atmosphere. Many VOCs are formed by incomplete combustion of organic materials, and tobacco is not the only source of exposure. Although VOCs are also present in foods and beverages, the levels of many VOCs and VOC metabolites are elevated in smokers’ urine compared with nonsmokers. Several VOCs in tobacco smoke, including acrolein, benzene, and 1,3-butadiene, can cause cardiovascular and lung damage. 1,3-butadiene is also a human carcinogen and benzene is a human carcinogen known to cause leukemia. A number of harmful VOCs and their metabolites can be measured in human blood, urine, and breath and those biomarkers serve as a surrogate measure for tobacco smoke exposure.
While tobacco-specific biomarkers are useful for interim assessments of exposure, there are several sources of variation to consider when interpreting such data. These include frequency and intensity of tobacco use product type, inter- and intra-individual variability, biomarker/chemical half-life, and variability in lab methods. Differences in carcinogen exposure from different cigarette products could contribute to differences in smoking-associated cancer incidence. Due to the introduction of new tobacco-derived products and the development of novel ways to modify and use conventional tobacco products, biomarker studies can be used to assess relative harm of modified-risk tobacco products. For example, short-term observational studies have shown reduction in biomarker levels for VOCs, TSNAs, and PAHs in cigarette smokers who switched to e-cigarettes, smokeless or heated tobacco products. This suite of biomarkers has the potential to provide objective data on levels of nicotine as well as selected important carcinogens and toxicants that may be associated with use of novel tobacco products.
Selected Biomarkers of Exposure to Tobacco Products Toxicant Group Tobacco Constituents Biomarkers Clinical Relevance Nicotine Metabolites Nicotine Cotinine Addictive chemical Tobacco Specific Nitrosamines (TSNAs) 4-methylnitrosamino)-4-(3-pyridyl)-1-butanon (NNK) 4-methylnitrosaminol)-4-(3-pyridyl)-1-butanol (NNAL) Carcinogen Polycyclic Aromatic Hydrocarbons (PAHs) Naphthalene and Pyrene 2-Napthol and 1-Hydroxypyrene Possible human carcinogens Volatile Organic Compounds (VOCs) Acrylonitrile, acrolein, acrylamide CYMA, CEMA, AAMA Probable human carcinogens Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
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IBS11 - Electronic Cigarettes and Heat-Not-Burn Tobacco Products - How Are They Different (Ticketed Session) (ID 42)
- Event: WCLC 2019
- Type: Interactive Breakfast Session
- Track: Prevention and Tobacco Control
- Presentations: 1
- Now Available
- Moderators:
- Coordinates: 9/09/2019, 07:00 - 08:00, Amsterdam (2011)
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IBS11.01 - Electronic Cigarettes and Heat-Not-Burn Tobacco Products - How Are They Different (Now Available) (ID 3347)
07:00 - 08:00 | Presenting Author(s): Maciej L. Goniewicz
- Abstract
- Presentation
Abstract
Introduction: Although combustible tobacco cigarettes remain the most popular nicotine-containing products worldwide, non-cigarette products are evolving rapidly. Use of combustible tobacco remains the number one preventable cause of disease, disability, and death, however the effects of non-cigarette products on population-level health is unknown. Over the last 10 years electronic cigarettes (e-cigarettes) have gained considerable popularity, especially among smokers and youth. With the introduction of the ‘Heat-not-Burn’ (HnB) products (iQOS from Philip Morris International, Ploom TECH from Japan Tobacco International, and Glo from British American Tobacco) the landscape of tobacco product exposure has changed yet again.
Population studies: Some early models of HnB products were developed in the late 1980s; however they did not reach a significant number of consumers and were withdrawn from the market. The introduction of HnB products in Japan in 2014 has been accompanied by an enormous decline in combustible cigarettes. Results from an international survey (International Tobacco Control (ITC) project) showed that that a high percentage of respondents believed HnB and e-cigarettes to be less harmful than cigarettes. Interestingly, smokers in Japan were most likely of 22 countries to believe that HnB were less harmful than cigarettes. Relative harmfulness beliefs of HnB may be both a cause and an effect of their popularity in Japan, fueled by marketing efforts. Ongoing studies will relate these beliefs to reasons for using HnB products, and, with future cohort data, transitions to/from HnB and cigarettes. Concerns have been raised that novel HnB tobacco products may be appealing to youth. Our research have showed that awareness and interest in HnB products among youth in Canada, England and USA was stable between 2017 and 2018, and concentrated primarily among smokers. Perceptions of HnB products are more similar to e-cigarettes than combustible tobacco.
Toxicity: HnB tobacco products purport to deliver nicotine while reducing exposure to toxicants compared with combustible nicotine products such as tobacco cigarettes by avoiding directly burning tobacco and instead heating tobacco. We measured nicotine in HnB product and found that it delivered 1.4 mg nicotine from a single cartridge, while e-cigarette and tobacco cigarettes delivered 1.3 mg and 2.1 mg nicotine, respectively. In conventional cigarettes, once tobacco is heated above 600°C, combustion occurs, and smoke containing harmful chemicals is released. HnB have an electrical heating component, like e-cigarettes, that heats processed tobacco to 350°C releasing volatile components that often are not detectable in e-cigarettes. In general, yields of carbonyl and aromatic compounds and amines (except for nicotine) in HnB products have been shown to be between one and two orders of magnitude lower than yields of combustible cigarettes, but relatively similar to those of e-cigarettes. Hypothetically, reducing the aerosol generation temperature can result in lower emissions of tobacco combustion byproducts and reduced toxicity as compared to conventional tobacco cigarettes. Although many combustion by-products may be eliminated in HnB devices, carcinogenic nitrosamines are generated in the process of tobacco curing rather than during combustion, and may be transferred from the HnB into the aerosol that it generates. Our group tested nicotine and four Tobacco-Specific Nitrosamines (TSNAs), potent lung carcinogens, in HnB product iQOS. We compared TSNA levels in aerosols from HnB, e-cigarette and cigarette smoke. TSNA yields were significantly higher in the HnB product than those found in e-cigarettes but significantly lower than those found in tobacco cigarettes. TSNA yields in a smoke from single tobacco cigarette were between 7-17 times higher than TSNA yields in emissions from a single HnB cartridge.
Potential health effects: Claims of lowered risk or health benefits for HnB compared to conventional cigarettes are based almost exclusively on industry-funded research, and except limited number of product testing studies, independent research is not available to support these claims as of 2019. To determine the cytotoxic and proinflammatory effects of HnB products, we exposed bronchial epithelial cells aerosol generated from HnB, e-cigarette aerosol, tobacco smoke or air (control) using an air–liquid interface system. Exposure to HnB resulted in decreased cell viability and increased release of pro-inflammatory interleukins as compared to air controls. Tobacco cigarette was the most toxic product. Interestingly, HnB product showed reduced toxicity as compared to tobacco cigarettes but increased toxicity compared to e-cigarettes. Finally, we used animal model to evaluate if short term in vivo exposure to HnB aerosols has the potential to recruit immune cells into the lung. We exposed mice to emissions from HnB, e-cigarette, and tobacco cigarettes. After 2-week exposure, we have made the novel observation that there was a hierarchy in the inflammatory response in the lung following exposure to the different products, with tobacco cigarettes causing the strongest and e-cigarette the weakest responses.
Summary: HnB are different from conventional cigarettes and overall appears to deliver less of some toxicants. It is currently not clear whether HnB products may pose lower, the same or higher health risks than combustible cigarettes depending on the disease. HnB products emit more of several important toxicants and carcinogens with more adverse health effects than e-cigarettes.
Comparison of tobacco cigarettes, Heat-Not-Burn (HnB) products, and e-cigarettes. Tobacco Cigarettes (TC) Heat-not-Burn (HnB) E-cigarettes (EC) Nicotine YES YES YES (most products) Tobacco YES YES NO Combustion YES NO NO Temperature YES (very high during puffs) YES (lower than TC) YES (lower than TC; can be overheated)
Electronic system NO YES YES Relative risk (hypothetical) Higher than HnB and EC Lower than TC but higher than EC
Lower than TC and HnB Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
