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Public Health Consequences of E-Cigarettes (2018)

Chapter: 10 Cancers

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Suggested Citation:"10 Cancers." National Academies of Sciences, Engineering, and Medicine. 2018. Public Health Consequences of E-Cigarettes. Washington, DC: The National Academies Press. doi: 10.17226/24952.
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10 Cancers In prior Surgeon General reports, active smoking of combustible tobacco cigarettes has been determined to be causally associated with increased risk of 13 different malignancies (HHS, 2014). The biological mechanisms driving combustible tobacco cigarette smoking as a cause of such a diverse spectrum of cancers is due in large part to the wide array of carcinogens present in combustible tobacco cigarette smoke, many of which are generated by the combustion of the tobacco. There are more than 7,000 chemicals in combustible tobacco cigarette smoke, and more than 70 are established human carcinogens (HHS, 2010; IARC, 2012). In addition to combustible tobacco cigarette smoking, pipe and cigar smoking are established causes of lung cancer (HHS, 2014). Fur- thermore, even exposure to secondhand tobacco smoke, which results in much lower levels of smoke exposure than active smoking, is causally associated with lung cancer (HHS, 2006). The cancer risk associated with the use of electronic cigarettes hypo- thetically would be expected to be less than combustible tobacco cigarettes based on the rationale that e-cigarettes include nicotine from tobacco— but not all the other tobacco constituents—and would therefore result in a reduced burden of carcinogens delivered to the user. Additionally, the nicotine present in e-cigarette aerosols does not contain appreciable amounts of tobacco-specific nitrosamines, nor are other pyrolysis prod- ucts from nicotine formed. Moreover, compared with combustible tobacco smoke, potentially carcinogenic components of e-cigarette aerosols may be orders of magnitude less “carcinogenic” compared with those present 381

382 PUBLIC HEALTH CONSEQUENCES OF E-CIGARETTES in tobacco smoke (Chen et al., 2017; Stephens, 2018). (Comparisons of combustible tobacco smoke and e-cigarette aerosols are described in more detail in Chapter 18 on Harm Reduction.) By contrast, there is uncertainty about the potential mutagenicity and carcinogenicity of other e-cigarette substances, such as flavorants and humectants, present in the aerosol emitted from e-cigarettes that result from the heating and aerosolization of the liquid in these products. Furthermore, as described in Chapter 5, carcinogens such as formaldehyde and arsenic have been detected in electronic cigarette aerosol. CHARACTERIZATION OF DISEASE ENDPOINTS AND INTERMEDIATE OUTCOMES As shown in Figure 10-1, the etiology of cancers induced by envi- ronmental exposures is a complex, multistep process that generally takes years to develop. There are several biologically plausible pathways for FIGURE 10-1  Conceptual framework of plausible pathways, including mecha- nisms and intermediate outcomes, by which exposure to e-cigarettes influences cancer outcomes. NOTE: ROS = reactive oxygen species.

CANCERS 383 which components of e-cigarette aerosols could conceptually influence cancer development. As discussed in Chapter 5, numerous compounds identified in e-cigarette aerosols can form reactive oxygen species (ROS), and/or can be converted to reactive intermediates capable of binding to DNA. Oxidative damage to DNA, and/or the direct adduction of reac- tive molecules to DNA, such as can occur with formaldehyde, is the most important intermediate outcome of chemical carcinogenesis. As discussed later in this chapter, some studies have identified cytotoxicity of e-cigarette aerosols, potentially contributing to tissue repair and mitogenic response, which is another important pathway in the development of chemically induced cancers. Formaldehyde is perhaps the most prevalent compo- nent of e-cigarette aerosols capable of inducing ROS formation. A 2014 National Research Council report on the carcinogenesis of formaldehyde determined that epidemiological evidence was ­ trongest for an associa- s tion between formaldehyde exposure and cancers of the naso­ haryngeal p region and sinonasal cavities and myeloid leukemia (NRC, 2014). How- ever, it should be recognized that formaldehyde is highly reactive, and potential DNA damage induced by it is most likely to occur at the site of exposure, the upper airways. It is also formed in small amounts by endogenous processes, so whether toxicologically significant amounts of formaldehyde from exogenous exposures can cause DNA damage in tissues distant from the site of exposure is controversial (Swenberg et al., 2011). Nevertheless, the presence of levels of formaldehyde in e-cigarette aerosols at concentrations that reportedly can exceed occupational expo- sure limits by an order of magnitude or more (see Chapter 5) are of con- cern for the potential risk to nasopharyngeal and lung cancer. It should be noted that, as described in earlier chapters, the levels of formaldehyde in e-cigarette aerosols can vary by many orders of magnitude, depend- ing in large part on the device parameters (e.g., power), e-liquid contents (e.g., propylene glycol [PG] and glycerol), and user characteristics (e.g., puff topography). Thus, the presence of formaldehyde and other poten- tially mutagenic and cytotoxic constituents provides biologically relevant mechanisms whereby long-term use of e-cigarettes could affect cancer risk. OPTIMAL STUDY DESIGN The strongest evidence to characterize the potential association between e-cigarette use and the risk of human cancer will be methodologi- cally rigorous epidemiological studies with human cancer as the outcome. Importantly, many e-cigarette users will be current or former combustible tobacco cigarette smokers, especially in the near term, and the effects of current and former smoking will be a challenging confounder to account

384 PUBLIC HEALTH CONSEQUENCES OF E-CIGARETTES for in observational studies. The second strongest level of evidence will be studies of intermediate cancer endpoints; for example, a study of e-cigarette use in relation to colorectal adenomas would have direct rel- evance to colorectal cancer because adenomas are precursor lesions in the colon carcinogenesis pathway. An important result of this comprehensive review is that the published literature is currently devoid of any evidence that includes rigorously designed epidemiological studies that include intermediate cancer endpoints, let alone cancer as an endpoint. Except for a study that included self-reported cancer as an adverse event (Manzoli et al., 2017), the published data have used biomarkers (oxidative stress and inflammation) as study outcomes. EPIDEMIOLOGY The literature search identified two studies on e-cigarette products in humans that refer to cancer. One of these was the study by Manzoli and colleagues (2017), which was composed of three groups (total n = 932) with the following sample sizes at the end of the 24-month follow-up: smokers of only combustible tobacco cigarettes throughout follow-up (n = 363), users of only e-cigarettes throughout follow-up (n = 97), and users of both e-cigarettes and combustible tobacco cigarettes throughout follow-up (n = 37). The authors defined e-cigarette users as users of any type of e-cigarette for 6 months or more. The authors report “any cancer” under serious adverse events, with the following results: only combus- tible tobacco cigarettes 0.8 percent (3/363), only e-cigarettes 2.1 percent (2/97), and dual users, 0 percent (0/37). The risk ratios the committee calculated from these data, using combustible tobacco cigarettes only as the referent category, are 2.49 (95% CI = 0.42–14.72) for e-cigarettes only and 0 (95% CI not estimable) for dual use. The results do not provide any indication for cancer risk reduction from sole use of e-cigarettes. These data are extremely limited by sample size and are of low quality; for example, the cancer data are presumably self-reported and not pathologi- cally confirmed, the sample size is very small to assess the endpoint of any cancer and precludes assessment of specific malignancies, and there is no consideration of complete combustible tobacco cigarette smoking history or potential confounding factors. In another human study, oral cells were collected by scraping the oral mucosa; the micronucleus assay was then applied to these oral mucosa cells (Franco et al., 2016) as a biomarker of potential genotoxicity and/ or chromosomal instability (Luzhna et al., 2013). The Franco and col- leagues (2016) study population had a total of 65 participants from three groups: (1) combustible tobacco cigarette smokers (n = 23); (2) e-cigarette users (defined as use of any e-cigarette device and liquid; n = 22); and

CANCERS 385 (3) non-smokers of combustible tobacco cigarettes and e-cigarettes (n = 20). The results revealed that compared with non-users of e-cigarettes and non-smokers of combustible tobacco cigarettes, the mean number of micronucleated cells/1,000 cells was 21 percent higher in e-cigarette users and 160 percent higher in combustible tobacco cigarette smokers. The results were also presented for the measure of total micronuclei/1,000 cells; compared with non-smokers of combustible tobacco cigarettes and e-cigarettes, e-cigarette users had mean levels that were 133 percent higher and combustible tobacco cigarette smokers had mean levels that were 633 percent greater. The pattern of associations for both micronuclei measures presented were thus consistent in showing that the average micronuclei burden was elevated in e-cigarette users relative to that in never smokers, and was elevated fourfold or more in combustible tobacco cigarette smok- ers compared with e-cigarette users. The only p-values reported were for the comparison of combustible tobacco cigarette smokers with e-cigarette users; these differences were statistically significant for both mean micro- nucleated cells/1,000 cells (p = 0.001) and total micronuclei/1,000 cells (p = 0.004). Weaknesses of this study include not presenting any evidence on the reliability of the micronucleus assay, not presenting all relevant p-values, and the lack of consideration of potential confounding factors even though the e-cigarette user group was on average 10 years older than the other study groups. This latter point is important because other studies have demonstrated age-related associations with micronuclei for- mation (Bonassi et al., 2011; Fenech et al., 2011). Also relevant to a consideration of the potential association between electronic cigarettes and cancer are studies of e-cigarette use in relation to oxidative stress and inflammation; both of these biomarkers have been reviewed in detail earlier in this report. For the study of oxidative stress, the detailed results were not presented, but the graphical evidence pre- sented failed to show a clear association between active and passive combustible tobacco smoking or active and passive e-cigarette use on acute measures of oxidative stress in an experimental setting (Poulianiti et al., 2016). A major limitation of the study by Poulianiti and colleagues is that the well-established role of combustible tobacco cigarette smoking in increasing oxidative stress (HHS, 2004, 2010) was not observed, raising major questions about the study’s validity. Whether this was due to prob- lems with the research protocol or suboptimal assay quality is unclear. The study of inflammation (Flouris et al., 2012) was embedded within the exact same study as the aforementioned study of oxidative stress (Poulianiti et al., 2016), in that it was the identical study population except the assay results were presented for markers of inflammation (i.e., same study, two different publications). Once again, the complete results were not presented, but the authors reported that under the experimental con-

386 PUBLIC HEALTH CONSEQUENCES OF E-CIGARETTES ditions, both active tobacco smoking and secondhand exposure to tobacco smoke were significantly associated with increased circulating concentra- tions of inflammatory markers, including leucocytes, lymphocytes, and granulocytes (Flouris et al., 2012). These associations are consistent with the known effects of tobacco smoke exposure (HHS, 2004, 2010), and thus these findings suggest greater internal validity than for the oxidative stress results from this exact same study. The results did not show simi- lar associations with e-cigarettes, which were not associated with these inflammatory markers. CASE REPORTS AND OTHER CLINICAL STUDIES Two case reports were identified that provided evidence relevant to the association between e-cigarette use and cancer. One case reported on a white male combustible tobacco cigarette smoker who had chronically elevated leucocyte and neutrophil counts in the absence of overt clinical disease; this is a clinical scenario consistent with chronic idiopathic neu- trophilia (Farsalinos and Romagna, 2013). The patient was followed clini- cally for 6.5 years, during which he was unable to quit smoking and the symptoms persisted. The patient was then able to successfully quit smok- ing by using e-cigarettes. Even though the patient still used e-cigarettes after he stopped smoking combustible tobacco cigarettes, 6 months after quitting the latter, all the patient’s markers of inflammation were sig- nificantly reduced, including leucocytes, lymphocytes, neutrophils, and C-reactive protein (Farsalinos and Romagna, 2013). Case reports provide only a weak form of evidence, but this single patient’s experience suggests that e-cigarettes have less detrimental impacts than combustible tobacco cigarettes on inflammation and immune status. In a case report published by Madsen and colleagues (2016), a 45-year- old female who used e-cigarettes presented after experiencing abdominal pain and fever for 4 months. Radiographic images revealed numerous pulmonary nodules and liver lesions consistent with extensive metas- tasis, but after a complete clinical workup, no evidence of malignancy was detected. A lung biopsy found an area with multinucleated giant cells. The authors reported that the biopsied lesion was consistent with a foreign-body reaction to lipophilic material. The patient subsequently stopped use of e-cigarettes; shortly thereafter, the lung nodules and liver lesions disappeared. The authors noted that the presence of multinucle- ated giant cells was consistent with the presence of glycerol-based oils detected in e-cigarette aerosol, and concluded that using e-cigarettes was associated with an inflammatory reaction that produces symptoms that can create the appearance of metastatic cancer. These two case reports both relate to inflammation/immune sta-

CANCERS 387 tus, with the case report of Farsalinos and Romagna (2013) suggesting that e-cigarettes are associated with substantially less inflammation than combustible tobacco cigarettes. However, the case report of Madsen and colleagues (2016) indicated that e-cigarettes are a strong enough source of inflammation to elicit symptoms that could be misdiagnosed as a form of cancer. These case reports raise interesting questions and ­einforce r the long-term need for carefully designed epidemiological studies of ­ e-cigarette use in relation to cancer risk that include appropriate com- parisons based on jointly considering the use of combustible tobacco cigarettes and e-cigarettes. IN VIVO ANIMAL STUDIES The literature search identified no in vivo animal studies focused on the potential carcinogenic actions of long-term e-cigarette use (Dodmane et al., 2014; Haussmann and Fariss, 2016; Toth, 1982; Waldum et al., 1996). In Vitro Mutagenicity by the Ames Salmonella Reverse Mutation Assay Three studies used the Ames mutagenicity assay with and without S9 metabolic activation (Canistro et al., 2017; Misra et al., 2014; Thorne et al., 2016) (see Table 10-1). Canistro and colleagues (2017) evaluated urine from male rats exposed in vivo to e-cigarette aerosols. They used two different Salmonella strains: TA100, which detects predominantly base substitution mutations, and YG1024, which detects primarily frame-shift mutations. They found that urine from e-cigarette aerosol-exposed rats was directly mutagenic in TA100, and metabolic activation decreased mutagenicity in this strain. Conversely, they found that urine was not directly mutagenic in YG1024 strain, but addition of the metabolic activation system sig- nificantly increased mutagenicity of urine above the background rate in non-exposed rats. Thorne and colleagues (2016) directly tested e-cigarette aerosol collected matter (ACM) from a Vype® ePen e-liquid cartridge containing blended tobacco flavor in TA98 and TA100 strains, with and without metabolic activation at nine different concentrations, up to 2,400 µg/plate. They reported no significant increases in mutagenicity in any of the assays. Misra and colleagues (2014) also assessed two e-liquids for mutagenicity in Ames strains TA98 and TA100, with and without metabolic activation. While extracts from tobacco smoke from standard reference combustible tobacco cigarettes were mutagenic in both strains at higher concentrations (in the presence of S9), there was no increase in mutagenicity in either strain exposed to the e-cigarette aerosol extract at any dose. Thus, of three studies examining mutagenicity of e-liquids, the

388 PUBLIC HEALTH CONSEQUENCES OF E-CIGARETTES TABLE 10-1  In Vitro Mutagenicity/DNA Damage Assessment of E-Cigarette Liquids and Aerosols Reference Test Agents Cells or Tissue Types Breheny et al., 2017 Vype ePen e-liquid Bhas 42 mouse fibroblast cartridges (blended cells. tobacco flavor) containing 18 mg/ml nicotine; comparison with tobacco smoke total particulate matter (TPM) from reference combustible tobacco cigarette (3R4F). Canistro et al., 2017 e-cigarette BandZ S.r.l., Blood and urine collected (Pisa, Italy). “Essential from in vivo animal cloud, red fruit flavor,” exposures; male S-D rats 20-ml package. exposed via inhalation Composition per 100 g of chamber. product: propylene glycol, Peripheral blood for glycerol, nicotine (18 mg/ alkaline comet assay and ml). Power set at 5.5 V, micronucleus test. 15 W. DNA extracted from lung. Urine for Ames assay, Salmonella strains TA100 and YG1024 with and without S9. Misra et al., 2014 blu e-cigarettes containing Salmonella strains TA98 and glycerol-based e-liquids, TA100. with and without nicotine CHO-K1 cells. and two market leader flavors (classic tobacco and magnificent menthol), were used. Combustible tobacco cigarettes (Kentucky reference 3R4F, 1R5F, and Marlboro Gold), were used for comparison.

CANCERS 389 Dose and Time Course Assay Employed Results Aerosol collected “Promoter activity” via ACM from the e-cigarette material (ACM) from the cell transformation assay. was shown to be negative e-cigarette was produced in all three promoter using a Borgwaldt experiments, whereas TPM LM20X linear smoking was positive in all three machine with 3-second experiments. duration using a square- wave puff profile, 55-ml puff volume, 30-second frequency, 3-second puff duration. ACM concentrations 3, 6, 12, 24, 48, 60, and 120 µg/ ml. Comparison to same concentrations of TPM. Equivalent to 1 ml/ Alkaline comet assay on “Extensive DNA damage day e-liquid. One cycle blood. in leukocytes measured of treatment consisted Micronucleus test on as tail comet length of of 17-second puff (6 smears of peripheral the fragmented DNA seconds on, 5 seconds off, blood. determined by single- and 6 seconds on) followed 8-OHdG (oxidative double-strand breaks.” by 20-minute stop. At damage to DNA). “Increase in the percentage the end of the cycle, the Ames test on urine of immature micronucleated animals were transferred extracts. reticulocytes (MN-RET) over to a clean chamber to normal reticulocyte RT.” begin the next cycle. “8-OHdG markedly Animals were submitted increased in the lungs.” to 11 cycles per day “Urine of e-cig-exposed for 5 consecutive days animals induced a dose- per week, and for 4 dependent increase in the consecutive weeks. number of S. typhimurium revertants in different strains. The highest sensitivity was shown by the TA100 strain.” Cells were treated for Ames assay TA98 and No significant induction in approximately 24 hours TA100 with S9 activation. the number of revertants with increasing levels of Micronucleus assay. over respective controls was e-liquids. The cellular observed for all e-liquids. treatment dose range No significant induction used for e-cigarettes in the MN formation over (e-liquids and pad- respective controls was collected aerosols) was observed for all e-liquids. 0–20 mg/ml and for combustible tobacco cigarettes, 0–0.5 mg/ml. continued

390 PUBLIC HEALTH CONSEQUENCES OF E-CIGARETTES TABLE 10-1  Continued Reference Test Agents Cells or Tissue Types Thorne et al., 2016 E-cigarette ACM from Salmonella strains TA98 and Vype® ePen e-liquid TA100. cartridges (blended tobacco flavor) contained 18 mg/ml nicotine. Thorne et al., 2017 Emissions of three aerosol Human bronchial epithelial products. Kentucky cells (BEAS-2Bs). reference combustible tobacco cigarettes (3R4F) and 2 e-cigarette formats: (1) a puff-activated closed “cigalike” device (eStick); (2) a “closed modular” system, dual-voltage, button-activated product (ePen). Welz et al., 2016 E-liquids with the fruit Fresh tissue samples flavors apple and cherry of healthy human and one tobacco-flavored oropharyngeal mucosa as­ liquid; base mixture of sembled into mucosal tissue 80% propylene glycol, 10% cultures (spheroidal in vitro glycerol, and 10% water. model). All liquids had a nicotine concentra­ ion of 12 mg/ t ml. Yu et al., 2016 V2 e-cigarette in red Immortalized human American tobacco flavor keratinocytes (HaCaT). and VaporFi e-cigarette HNSCC cell lines in classic tobacco flavor; UMSCC10B and HN30. both brands used a mixture of 70% propylene glycol/30% glycerol liquid formulas. Both 1.2% (12 mg/ml) nicotine e-liquid and nicotine-free versions in the same flavors were used for each.

CANCERS 391 Dose and Time Course Assay Employed Results All TPM/ACM Ames assay TA98 and Non-mutagenic in the 85- experiments were TA100 with S9 activation. mm plate incorporation conducted using final assay. concentrations of 0, 50, 100, 150, 200, 250, 300, 500, 1,000 and 2,400 µg/ plate. Average Delivered DNA double strand eStick and ePen were non- Deposition (µg/cm2). breaks (γ-H2Ax genotoxic and non-cytotoxic. immunofluorescence). Combustible tobacco 3R4F  0 cigarette smoke aerosols     3.1 ± 0.3 were genotoxic at a 3.1-µg/     5.4 ± 1.8 cm2 dose and cytotoxic at     10.5 ± 1.2 26.9 µg/cm2.     26.9 ± 2.1 eStick  0     35.2 ± 0.9     71.3 ± 2.0 ePen  0     42.5 ± 4.1     85.7 ± 2.7 Two different types of Alkaline elution DNA Tobacco liquid and base incubation: (1) one-time damage assay liquids were negative when incubation for 24 hours (neutral comet assay) treated once for 24 hours or and (2) incubation for 2.5 when treated for 5 days. By hours on five sequential contrast, apple and cherry days. DNA-damage liquids induced significant experiments used one DNA damage in both dose, a 15% solution of single and repetitive 5-day each e-liquid. treatments. Single concentration Neutral comet assay All four e-cigarette extracts 1% aerosol by volume. DNA double strand breaks (both nicotine and non- HaCaT cells treated for 8 (γ-H2Ax nicotine) were positive, in weeks. immunofluorescence). all three cell types; nicotine UMSCC10B and HN30 response greater. each treated for 1 week.

392 PUBLIC HEALTH CONSEQUENCES OF E-CIGARETTES two that looked directly at the e-liquid extracts did not find any evidence of mutagenicity, although the study that exposed animals (rats) in vivo to e-cigarette aerosols did find an increase in the mutagenicity of urine. Micronucleus Assay Both Canistro and colleagues (2017) and Misra and colleagues (2014) used the micronucleus assay to assess potential mutagenicity of e-liquids. The micronucleus assay detects clastogenic and aneugenic DNA damage that results in the disruption or breakage of chromosomes, leading to portions of the chromosome being added, deleted, or rearranged follow- ing cell division. Canistro and colleagues (2017) found an increase in the percentage of micronucleated reticulocytes (immature red blood cells) following in vivo exposure to e-liquids. In contrast, Misra and colleagues (2014) found no significant increase in Chinese hamster ovary (CHO) cells exposed to e-liquids for 24 hours, including cells exposed to tobacco smoke extract. Again, although the same endpoint assay was used in each of these studies, the differences in outcomes may be due to substantial differences in experimental design, with the in vivo study of e-cigarette exposure finding a positive effect, whereas the study in a cell line exposed directly to e-liquids had no effect. Oxidative Damage to DNA (8-OHdG Formation) Canistro and colleagues (2017) evaluated two measures of oxidative stress following in vivo, whole-body exposure of male Sprague-Dawley rats to the equivalent of 1 ml/day of e-liquid containing 18 mg/ml of nic- otine in an inhalation chamber. Levels of 8-hydroxy-2′-deoxyguanosine (8-OHdG) in the lung, and the reducing power of the lung tissue (ferric reducing antioxidant power, or FRAP) were assessed in the animals after 4 consecutive weeks of exposure via a smoking machine (11 17-­ econd s puff cycles per day, 5 days per week). The formation of 8-OHdG is a widely used biomarker of oxidative damage to DNA. It has been asso- ciated with increased mutagenesis in a number of test systems, and is often considered as an intermediate biomarker of carcinogenic potential (Curtin, 2012; Kasai, 1997). They found a statistically significant, approxi- mately fourfold increase in the levels of 8-OHdG in the lung tissue of exposed rats. There was a strong inverse correlation between the FRAP activity in lung tissue and 8-OHdG levels (r = 0.845, n = 5), further supporting the conclusion that e-cigarette aerosols increase oxidative stress in the lung. The authors also measured the levels of antioxidant enzymes, including catalase, NQO1, superoxide dismutase, and gluta- thione S-transferase, and found a 25–35 percent decrease in activities in

CANCERS 393 all four enzymes. Because the expression of these enzymes is driven in large part by the levels of antioxidant “stress” through the Keap1-Nrf2/ antioxidant response element, an increase in oxidative stress would nor- mally be expected to increase, rather than decrease, the levels of expres- sion of these enzymes’ pathway (Ma, 2013). It is not clear why the levels of these enzymes would be decreased, rather than increased, following exposures to e-cigarette aerosols that appear to be inducing oxidative stress in the lung. Although oxidative damage to DNA is widely regarded as a poten- tially significant contributor to carcinogenesis, the vast majority of oxi- dative damage to DNA occurs via endogenous processes. The extent to which exogenous factors that induce oxidative stress and thus the forma- tion of 8-OHdG contribute to actual tumor development is uncertain, and thus the utility of 8-OHdG to serve as a predictive biomarker of carcino- genesis is very limited. Cell Transformation (Promoter Activity) Although most in vitro assays focused on evaluating carcinogenic potential of xenobiotics use mutagenesis and/or oxidative free radical production, a few in vitro tests can assess the potential for a substance to act as a promoter of carcinogenesis. Breheny and colleagues (2017) used a cell transformation assay to assess the potential promoter activity of e-cigarette–generated ACM, and compared it to the promoter activity from tobacco smoke total particulate matter (TPM) collected from a ref- erence combustible tobacco cigarette (3R4F). ACM was collected from a Vype ePen with an e-liquid cartridge containing blended tobacco flavor and 18 mg/ml of nicotine, using a linear smoking machine. Seven differ- ent ACM concentrations, ranging from 3 to 120 µg ACM/ml, were used in exposures to Bhas 42 mouse fibroblasts. They found that TPM was posi- tive in all of three experiments, whereas ACM was negative in all three experiments (see Table 10-1). Relevance of DNA-Damage/Mutagenicity Studies and the Presence of DNA-Reactive Chemicals in E-Cigarette Aerosols to Potential Human Cancer Risk from E-Cigarette Use As discussed above, some of the in vitro studies have found evi- dence that chemical constituents of e-cigarette aerosols are capable of reacting with DNA and in some instances inducing mutations in vitro and following in vivo exposure (Canistro et al., 2017). Some of the chemi- cal constituents found in e-cigarette aerosols, including especially the reactive aldehydes formaldehyde and acrolein, are DNA-reactive, and

394 PUBLIC HEALTH CONSEQUENCES OF E-CIGARETTES formaldehyde has been shown to cause nasopharyngeal cancers in ani- mals exposed via inhalation, and is considered by the Environmental Protection Agency and the International Agency for Research on Cancer to be a “known human carcinogen.” Although highly reactive with both protein and DNA, acrolein to date has not been shown to be carcinogenic in laboratory animals following long-term exposure via ingestion. How- ever, no long-term inhalation studies in laboratory animals have been completed. As discussed in Chapter 5, formaldehyde and acrolein are present in e-cigarette aerosols. It should be noted that both of these reac- tive aldehydes are formed endogenously at low levels, and are present in many food items and may “off-gas” from commercial products, leading to frequent and widespread, but low-level, exposures to these compounds. It should also be noted that both acrolein and formaldehyde are highly reactive, and adverse health effects, including potentially cancer, are most likely to occur at the site of exposure (e.g., in the oral cavity and tracheo- bronchial tree). Cancer risk from environmental exposures to potentially DNA-reactive/mutagenic chemicals is a function of dose of the chemical at the target site. Using formaldehyde as an example, it is informative to put the levels of formaldehyde in e-cigarette vapors in perspective with other sources of exposure. As discussed in Chapter 18 (Harm Reduc- tion), Goniewicz (2014) measured the levels of formaldehyde and other carbonyl compounds in e-cigarettes and compared them with the levels present in combustible tobacco cigarettes. When adjusted to “cigarette equivalents” (amount emitted in one combustible tobacco cigarette, and amount present in 15 “typical” puffs of an e-cigarette), the predicted exposures to both formaldehyde and acrolein were about 10- and 50-fold lower from e-cigarettes in most circumstances (see Table 10-2). Gillman and colleagues (2016) did a similar comparison, using five different devices, each at four different “power” levels. Two of these devices generated remarkably high levels of both formaldehyde and acrolein—levels well above those found in cigarette smoke, and levels that exceed occupational standards for both of these substances (see Table 10-3). They noted that these two devices likely suffered from poor “wicking” of e-liquid to the heating element, which would generate much higher temperatures, facilitating decomposition of the humectant (PG) to carbonyls. They also noted that device 1 was not widely used, likely because of the frequency with which it would generate highly irritating aerosol (so-called “dry puff”). The other three devices generated levels of both formaldehyde and acrolein that were similar to those reported by Goniewicz and colleagues (2014). Furthermore, it should be recognized that the contributions of formal- dehyde, acrolein, and other reactive carbonyls present in cigarette smoke are likely relatively insignificant contributors to the known cancer risks

CANCERS 395 TABLE 10-2  Comparison of Formaldehyde and Acrolein Levels in Smoke from One Combustible Tobacco Cigarette and in Aerosol from 15 Puffs of an E-Cigarette Tobacco Smoke, 1 Cigarette E-Cigarette Aerosols per 15 Puffs (Roemer et al., 2004) (Goniewicz et al., 2014) Formaldehyde Acrolein Formaldehyde Acrolein Mean 25.39 53.88 2.83 1.15 SD 21.80 31.81 1.82 1.35 Min  3.70 15.50 0.32 0.01 Max 75.50 98.20 5.61 4.19 Ratio cigarette/ 8.97 46.98 e-cigarette mean NOTE: SD = standard deviation. SOURCES: Adapted from Roemer et al., 2004, and Goniewicz et al., 2014. from combustible tobacco products. Thus, although there is substantial evidence that these DNA-reactive and potentially mutagenic compounds are formed and present in e-cigarette aerosols, the relatively low levels of exposure, coupled with the relatively low carcinogenic potential of these compounds, suggest that cancer risk from long-term use of e-cigarettes, if any, is likely to be very low, when compared with that from combustible tobacco cigarettes. STUDIES OF EFFECTS OF MAJOR COMPONENTS OF E-CIGARETTES ON CANCER OUTCOMES As described earlier regarding optimal study design, given the rela- tively recent introduction of e-cigarettes, there is a paucity of evidence on the long-term effects of e-cigarettes on cancer outcomes. Conse- quently, the committee drew on existing evidence of major components of e-cigarettes—namely, nicotine and the humectants PG and glycerol—with an emphasis on cancer outcomes. The committee discusses findings from epidemiological and in vivo animal studies in this section, from which the committee could draw inferences about the potential carcinogenic effects of e-cigarettes, but the discussion does not represent results of a systematic review.

396 TABLE 10-3  Formaldehyde and Acrolein Levels Generated from Five E-Cigarette Devices at Different Power Levels Units Adjusted to µg/15 Puffs Device 1 Device 2 Device 3 Device 4 Device 5 Power Level Form. Acro. Form. Acro. Form. Acro. Form. Acro. Form. Acro. P1 128 104 4 0.9 1.1 0.6 2.0 0.8 2.0 1.2 P2 315 255 23 5.0 1.1 0.9 4.2 0.9 3.2 2.4 P3 480 375 120 39.0 0.8 0.5 2.1 0.8 4.7 2.3 P4 765 615 255 124.5 8.9 8.0 3.2 0.9 5.1 2.4 Mean 422 337 100 42.3 2.9 2.5 2.9 0.8 3.7 2.1 SD 270 216 115 57.4 4.0 3.7 1.0 0.1 1.4 0.6 Min 128 104 4 0.9 0.8 0.5 2.0 0.8 2.0 1.2 Max 765 615 255 124.5 8.9 8.0 4.2 0.9 5.1 2.4 Ratio 0.1 0.2 0.3 1.3 8.7 21.8 8.9 65.3 6.8 26.1 NOTE: Acro. = acrolein; Form. = formaldehyde; SD = standard deviation. SOURCE: Adapted from Gillman et al., 2016.

CANCERS 397 Epidemiological Studies As reviewed below and elsewhere (Grando, 2014; HHS, 2014; IARC, 2000; Shields, 2011), the potential carcinogenicity of nicotine has been studied extensively in the in vitro and in vivo settings. However, there is a paucity of epidemiological evidence assessing the potential association between nicotine per se and the risk of cancer in humans. This is largely because studying the potential association between nicotine exposure and human cancer poses methodological challenges that severely compromise the generation of meaningful data. This is because prior to the advent of e-cigarettes, in recent decades the “purest” form of nicotine exposure has been via nicotine replacement therapies (NRTs). Given that these are smoking cessation medications, teasing an isolated contribution of NRTs in relation to cancer risk in the context of extensive prior/current combus- tible tobacco cigarette smoking histories is complex. For example, among smokers the overall contribution of nicotine exposure from NRT can only be expected to be a very small fraction of a smoker’s overall nicotine exposure because it will be greatly outweighed by the nicotine exposure from years of smoking combustible tobacco cigarettes. Continued greater use of NRT usually occurs in more addicted smokers who have a more difficult time quitting (Alberg et al., 2005), introducing the potential for strong confounding. With these inherent challenges, the Lung Health Study provides the highest quality evidence on this topic to date (Murray et al., 2009). The advantages of the Lung Health Study are that it was a smoking cessation trial that tested an NRT (nicotine gum) and thus had detailed NRT use and combustible tobacco cigarette smoking data in the intervention group for a period of 5 years. In this study 3,320 participants from this interven- tion group were followed up for an additional 7.5 years to ascertain cancer outcomes, thus providing evidence on this topic from a prospective cohort study that emanated from the original randomized trial. Despite these strengths, in addition to the generic limitations noted above are limita- tions introduced by the fact that the cohort size and duration of follow-up are limited for yielding adequate statistical precision, the nicotine doses from nicotine gum are small, and the NRT exposure use and assessment occurred so near in time to the follow-up for cancer outcomes that the study could only be expected to detect contributions that occur in the lat- ter stages of carcinogenesis. Thus, the inferences from the study results that indicated no statistically significant or clinically meaningful increased risk of lung cancer, gastrointestinal cancer, or all cancers are twofold: (1) it is unlikely there is a strong association between NRT use and cancer risk in the short term, and (2) the evidence provided by this null finding does not rule out the possibility of a weaker association between nicotine and cancer in the short term.

398 PUBLIC HEALTH CONSEQUENCES OF E-CIGARETTES No epidemiological studies have addressed the long-term health con- sequences, including cancer, of propylene glycol and glycerol. Despite the fact that propylene glycol has been widely used in theatrical settings and in a few other occupations (see Chapter 5), the absence of evidence on can- cer related to this topic is demonstrated by the fact that the Department of Health and Human Services, the International Agency for Research on Cancer, and the Environmental Protection Agency have yet to classify the carcinogenicity of propylene glycol in humans. In Vivo Animal Studies Typically, rodent bioassays for carcinogenesis involve 2 years of contin- uous exposures, and no studies of this nature have been identified in rats, mice, or other laboratory animals. However, N’-nitrosonornicotine (NNN) and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), derived from the tobacco leaves, formed during the tobacco curing process, and reported in e-liquids and aerosol, may contribute to the overall carcinogenic activity of tobacco products. As noted previously, however, because the nicotine in e-cigarette liquids is not extracted from cured tobacco leaves, where NNN and NNK are formed, the levels of these potent mutagens in e-cigarette aerosols are extremely low compared with tobacco smoke. Nicotine itself, as used in nicotine replacement therapies, is challenging to study in rela- tion to cancer risk in epidemiological studies; the one high-quality study to evaluate the potential carcinogenicity of nicotine in NRT, the Lung Health Study, yielded null findings (see Murray et al., 2009, above). Several studies have evaluated the consequences of long-term expo- sure to nicotine in animal models (Haussmann and Fariss, 2016). Two lifetime (2-year) bioassays evaluating the carcinogenicity of nicotine have been completed. Waldum and colleagues (1996) conducted a 2-year inha- lation exposure study of nicotine using young adult female rats exposed to a constant concentration (501 ± 151 µg/m3) of nicotine. Although more animals had tumors in the nicotine-exposed group (21/59; 36 percent) than the controls (6/25; 24 percent) (see Table 10-4), the types of tumors found in the exposed group were common in this strain of rat. The authors concluded that there were no “tumorigenic effects of nicotine on any organ in the body” (Waldum et al., 1996, p. 1345), although they did note that tumors in the pituitary gland (adenoma) were seen only in the nicotine-treated animals, and noted that nicotine has been shown to have “neuroendocrine actions” (Waldum et al., 1996, p. 1345). Toth (1982) evaluated the potential carcinogenic effects of lifetime exposure of 0.5 or 0.7 mg/ml of nicotine, administered in drinking water for 24 months to groups of male and female Swiss mice. These con- centrations translate to an average nicotine dose of approximately 150

CANCERS 399 TABLE 10-4  Occurrence of Tumors in Female Sprague-Dawley Rats Exposed to Nicotine for Up to 24 Months and Controls Tumors (Site and Type) Nicotine Exposed (%) Controls (%) Mammary gland Fibroadenoma 15 24 Adenocarcinoma 2 0 Pituitary gland Adenoma 7 0 Atypical adenoma 2 0 Ovary Granulosa-theca cell tumor 2 0 Adenocarcinoma 3 0 Skin Histiocytoma 2 0 Metastasis (origin unknown) Liver 2 0 Abdominal cavity 2 0 Total percentage of rats with tumors 36 (21/59) 24 (6/25) NOTE: Percentages may not add up to 100 percent due to varied reporting, rounding, and missing data from source. SOURCE: Adapted from Waldum et al., 1996. mg/kg per day assuming a body weight of 25 g. Due to higher water consumption in the low-dose group, the daily dose per mouse at the 0.5 mg/ml concentration was only slightly smaller than in the 0.7 mg/ml group. Although this was generally a well-designed study with a reason- ably large sample size, it could be argued that the highest dose was not sufficiently high, as there were no indications of toxicity, and no impact on body weight development or survival, so it would not be defined as a “maximal tolerated dose,” which is often an expectation in carcinogenic- ity bioassays. A thorough histopathological examination was completed. The authors reported no increase in tumor incidence in either nicotine- exposed group. The author of the study concluded that nicotine was “not carcinogenic under the experimental conditions” (Haussmann and Fariss, 2016, p. 712; Toth, 1982, p. 72). Murphy and colleagues (2011) evaluated whether nicotine adminis- tration could enhance the development of NNK-initiated lung tumors in A/J mice. They found that nicotine alone, administered at a daily dose of 0.15 mg/mouse for 46 weeks did not increase lung tumor multiplicity. NNK-treated mice had much higher lung tumor multiplicity compared

400 PUBLIC HEALTH CONSEQUENCES OF E-CIGARETTES with controls, but administration of nicotine for 46 weeks had no signifi- cant effect on the multiplicity of lung tumors in mice. Another recent in vivo study in rats investigated whether oral nicotine exposure could cause early histopathological changes in urinary bladder epithelium that might be consistent with early-stage bladder carcinogen- esis. Dodmane and colleagues (2014) administered nicotine hydrogen tar- trate to rats and mice at doses of 52 and 514 ppm, respectively, for 4 weeks in drinking water. They then did a detailed histological evaluation of the urothelial lining. They found histopathological changes (hyperplasia) in 70 percent of the rats and 40 percent of the mice, compared with none in control animals. They also found that rats had a non-significant increase in the mean BrdU labeling index relative to controls, although there was no evidence of cytotoxicity via scanning electron microscopy. The authors concluded that “these findings suggest that oral nicotine administration induced urothelial hyperplasia (increased cell proliferation), possibly due to a mitogenic effect of nicotine and/or its metabolites” (Dodmane et al., 2014, p. 49). They further hypothesized that such nicotine-induced urothe- lial cell proliferation could possibly “act synergistically with DNA adduct- forming aromatic amines to increase the incidence of tumor formation in the urinary bladder in tobacco users” (Dodmane et al., 2014, p. 53). VULNERABLE/SUSCEPTIBLE POPULATIONS Population characteristics that identify subgroups that bear a dis- proportionate burden of cancer in the United States are race/ethnicity, sex, and socioeconomic status. Among these, the groups with the highest cancer burden are African Americans, males, and those of lower socioeco- nomic status. When looking across these characteristics, African American males are a particularly high-risk group. Among African Americans, the use of NRT products has historically been very low (Fu et al., 2005, 2008; Trinidad et al., 2011), and the emerging surveillance data on e-cigarette use also indicate low prevalence of use by African Americans. The results of the literature search revealed that the few relevant human studies were largely or entirely carried out in predominantly white populations outside the United States. Future research that includes diverse U.S. populations will be essential. Children and adolescents are also vulnerable populations. For lung cancer, the younger the age of initiation of combustible tobacco cigarette smoking, the greater the risk of developing lung cancer in adulthood even after adjusting for lifetime combustible tobacco cigarette smoke exposure dose (HHS, 2014). This enhanced lung cancer risk associated with smok- ing at younger ages is hypothesized to be due to increased susceptibility

CANCERS 401 of the developing lung to carcinogens due to more rapidly dividing cells compared with mature lungs. SYNTHESIS A systematic review of the current body of evidence relevant to the potential association between electronic cigarette use and cancer leads to the clear conclusion that the present body of evidence is simply too sparse to permit meaningful inferences to be drawn about either cancer or inter- mediate cancer endpoints. Furthermore, the human studies published on cancer-related lines of inquiry to date are not only few in number, but have not had an optimal level of methodological rigor to permit drawing even preliminary inferences. The sparseness of the current evidence and the low quality of the human evidence on this topic preclude making any evidence-based conclusions about the potential association between e-cigarette use and risk of cancer in human populations. Finding: There are no available epidemiological studies on the potential association between e-cigarette use and cancer in humans to make any conclusions. This holds true for comparisons of e-cigarette use compared with combustible tobacco cigarettes and e-cigarette use compared with no use of tobacco products. Conclusion 10-1. There is no available evidence whether or not e-cigarette use is associated with intermediate cancer endpoints in humans. This holds true for e-cigarette use compared with use of com- bustible tobacco cigarettes and e-cigarette use compared with no use of tobacco products. Conclusion 10-2. There is limited evidence from in vivo animal stud- ies using intermediate biomarkers of cancer to support the hypothesis that long-term e-cigarette use could increase the risk of cancer; there is no available evidence from adequate long-term animal bioassays of e-cigarette aerosol exposures to inform cancer risk. Conclusion 10-3. There is limited evidence that e-cigarette aerosol can be mutagenic or cause DNA damage in humans, animal models, and human cells in culture. Conclusion 10-4. There is substantial evidence that some chemicals present in e-cigarette aerosols (e.g., formaldehyde, acrolein) are capable of causing DNA damage and mutagenesis. This supports the biologi- cal plausibility that long-term exposure to e-cigarette aerosols could

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Millions of Americans use e-cigarettes. Despite their popularity, little is known about their health effects. Some suggest that e-cigarettes likely confer lower risk compared to combustible tobacco cigarettes, because they do not expose users to toxicants produced through combustion. Proponents of e-cigarette use also tout the potential benefits of e-cigarettes as devices that could help combustible tobacco cigarette smokers to quit and thereby reduce tobacco-related health risks. Others are concerned about the exposure to potentially toxic substances contained in e-cigarette emissions, especially in individuals who have never used tobacco products such as youth and young adults. Given their relatively recent introduction, there has been little time for a scientific body of evidence to develop on the health effects of e-cigarettes.

Public Health Consequences of E-Cigarettes reviews and critically assesses the state of the emerging evidence about e-cigarettes and health. This report makes recommendations for the improvement of this research and highlights gaps that are a priority for future research.

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