A scoping review of the toxicity and health impact of IQOS.

This work aims to summarize the current evidence on the toxicity and health impact of IQOS, taking into consideration the data source. On 1 June 2022, we searched PubMed, Web of Science, and Scopus databases using the terms: 'heated tobacco product', 'heat-not-burn', 'IQOS', and 'tobacco heating system'. The search was time-restricted to update a previous search conducted on 8 November 2021, on IQOS data from 2010-2021. The data source [independent, Philip Morris International (PMI), or other manufacturers] was retrieved from relevant sections of each publication. Publications were categorized into two general categories: 1) Toxicity assessments included in vitro, in vivo, and systems toxicology studies; and 2) The impact on human health included clinical studies assessing biomarkers of exposure and biomarkers of health effects. Generally, independent studies used classical in vitro and in vivo approaches, but PMI studies combined these with modeling of gene expression (i.e. systems toxicology). Toxicity assessment and health impact studies covered pulmonary, cardiovascular, and other systemic toxicity. PMI studies overall showed reduced toxicity and health risks of IQOS compared to cigarettes, but independent data did not always conform with this conclusion. This review highlights some discrepancies in IQOS risk assessment regarding methods, depth, and breadth of data collection, as well as conclusions based on the data source.

A review of the toxicity of ingredients in e-cigarettes, including those ingredients having the FDA's "Generally Recognized as Safe (GRAS)" regulatory status for use in food.

INTRODUCTION: Some firms and marketers of electronic cigarettes (e-cigarettes; a type of electronic nicotine delivery system (ENDS)) and refill liquids (e-liquids) have made claims about the safety of ingredients used in their products based on the term "GRAS or Generally Recognized As Safe" (GRAS). However, GRAS is a provision within the definition of a food additive under section 201(s) (21 U.S.C. 321(s)) of the U.S. Federal Food Drug and Cosmetic Act (FD&C Act). Food additives and GRAS substances are by the FD&C Act definition intended for use in food, thus safety is based on oral consumption; the term GRAS cannot serve as an indicator of the toxicity of e-cigarette ingredients when aerosolized and inhaled (i.e., vaped). There is no legal or scientific support for labeling e-cigarette product ingredients as "GRAS". This review discusses our concerns with the GRAS provision being applied to e-cigarette products and provides examples of chemical compounds that have been used as food ingredients but have been shown to lead to adverse health effects when inhaled. The review provides scientific insight into the toxicological evaluation of e-liquid ingredients and their aerosols to help determine the potential respiratory risks associated with their use in e-cigarettes. IMPLICATIONS: The rise in prevalence of e-cigarette use and emerging evidence of adverse effects, particularly on lung health, warrant assessing all aspects of e-cigarette toxicity. One development is manufacturers' stated or implied claims of the safety of using e-cigarette products containing ingredients determined to be "Generally Recognized As Safe" (GRAS) for use in food. Such claims, typically placed on e-cigarette product labels and used in marketing, are unfounded, as pointed out by the United States Food and Drug Administration (FDA)1 and the Flavor and Extract Manufacturers Association (FEMA)2. Assessment of inhalation health risks of all ingredients used in e-liquids, including those claimed to be GRAS, is warranted.

Evaluating the Role of Nicotine Stereoisomer on Nicotine Pouch Abuse Liability: A Randomized Crossover Trial.

INTRODUCTION: Many oral nicotine pouch (ONP) brands use synthetic nicotine, which typically contains a racemic (50:50) mixture of nicotine's two stereoisomers: S-nicotine and R-nicotine. Because tobacco-derived nicotine contains more than 99% S-nicotine, the effects of R-nicotine in humans are not well known. We compared systemic nicotine exposure and product appeal of ONPs containing more than 99% S-nicotine versus racemic nicotine. AIMS AND METHODS: N = 18 adult smokers (Mage = 45 years, 66.7% male, 77.8% White) enrolled in a three-visit single-blind, randomized crossover study. During each visit, participants used one wintergreen-flavored, 3 mg nicotine ONP for 30 min following at least12 h nicotine abstinence. Study ONP #1 contained more than 99% S-nicotine and the other two study ONPs contained racemic nicotine (collapsed for analyses). Plasma nicotine assessments and measures of withdrawal relief occurred at t = 0, 5, 15, 30, 60, and 90 min; measures of product appeal were assessed following ONP use. RESULTS: Using the ONP with more than 99% S-nicotine resulted in greater plasma nicotine concentration from 15 to 90 min (p < .0001) and greater maximum plasma nicotine concentration than the ONPs with racemic nicotine (M = 9.9 ng/mL [SD = 2.5] vs. M = 5.7 ng/mL [SD = 2.8], respectively; p < .0001). Product liking and withdrawal relief were similar across ONPs, although participants reported more "bad effects" when using the ONP with more than 99% S-nicotine. CONCLUSIONS: Participants reported few subjective differences in ONPs according to nicotine stereoisomer, but plasma nicotine concentration was greater for ONPs using more than 99% S-nicotine. ONPs with more than 99% S-nicotine (vs. racemic nicotine) might be better substitutes for cigarettes, but research into other ONP characteristics (eg flavors, freebase nicotine) is needed to inform regulation. IMPLICATIONS: Little is known about the effects of racemic (vs. S-) nicotine in humans. In a sample of adults who smoke cigarettes, we identified that oral nicotine pouches containing racemic nicotine exposed participants to less nicotine than oral nicotine pouches containing only S-nicotine, but both types of oral nicotine pouches held similar, moderate appeal. Additional research evaluating the roles that flavorings, total nicotine concentration, and freebase nicotine play in the abuse liability of oral nicotine pouches would inform comprehensive product regulations to support public health.

Comparison of emissions across tobacco products: A slippery slope in tobacco control.

In this narrative review, we highlight the challenges of comparing emissions from different tobacco products under controlled laboratory settings (using smoking/vaping machines). We focus on tobacco products that generate inhalable smoke or aerosol, such as cigarettes, cigars, hookah, electronic cigarettes, and heated tobacco products. We discuss challenges associated with sample generation including variability of smoking/vaping machines, lack of standardized adaptors that connect smoking/vaping machines to different tobacco products, puffing protocols that are not representative of actual use, and sample generation session length (minutes or number of puffs) that depends on product characteristics. We also discuss the challenges of physically characterizing and trapping emissions from products with different aerosol characteristics. Challenges to analytical method development are also covered, highlighting matrix effects, order of magnitude differences in analyte levels, and the necessity of tailored quality control/quality assurance measures. The review highlights two approaches in selecting emissions to monitor across products, one focusing on toxicants that were detected and quantified with optimized methods for combustible cigarettes, and the other looking for product-specific toxicants using non-targeted analysis. The challenges of data reporting and statistical analysis that allow meaningful comparison across products are also discussed. We end the review by highlighting that even if the technical challenges are overcome, emission comparison may obscure the absolute exposure from novel products if we only focus on relative exposure compared to combustible products.

Influence of nicotine form and nicotine flux on puffing behavior and mouth-level exposure to nicotine from electronic nicotine delivery systems.

BACKGROUND: Nicotine form (freebase/protonated) and nicotine flux (rate at which nicotine is emitted) are two factors that can affect the dose of nicotine inhaled by individuals using electronic nicotine delivery systems (ENDS) because they can influence puffing behavior. The nicotine dose for each puff also is directly proportional to nicotine flux (i.e., dose/puff=nicotine flux*puff duration). This study examines the effect of nicotine form and flux on puffing parameters and mouth-level nicotine exposure. METHODS: Thirty-two dual ENDS and combustible cigarette participants completed five visits that differed by nicotine form (freebase or protonated) and nicotine flux (14 or 35µg/sec); a zero-nicotine condition was a negative control. Participants used a Subox Mini C ENDS, powered at 20W, during a 10-puff directed bout (B1) followed by a one-hour ad libitum bout (B2). Puffing parameters and mouth-level nicotine exposure were assessed using the American University of Beirut REALTIME instrument. RESULTS: Relative to protonated nicotine, freebase nicotine was associated with lower total puff duration (puff duration*number of puffs), lower flow rate in B1, lower liquid consumption, and lower mouth-level nicotine exposure. Increasing nicotine flux from 14 to 35µg/sec was associated with lower total puff duration in both bouts, as well as lower liquid consumption. Increasing nicotine flux was associated with higher mouth-level nicotine exposure in B1 only. CONCLUSION: ENDS with protonated nicotine may enhance nicotine exposure by promoting longer puffing and thus greater dose delivered. This work highlights the importance of accounting for interactions between nicotine form and flux when considering nicotine regulation for ENDS.

Nontargeted Analysis in Tobacco Research: Challenges and Opportunities.

Tobacco products are evolving at a pace that has outstripped tobacco control, leading to a high prevalence of tobacco use in the population. Researchers have been tirelessly developing suitable techniques to assess these products' emissions, toxicity, and public health impact. The nonclinical testing of tobacco products to assess the chemical profile of emissions is needed for evidence-based regulations. This testing has largely relied on targeted analytical methods that focus on constituent lists that may fall short in determining the toxicity of newly designed tobacco products. Nontargeted analysis (NTA), or the process of identifying and quantifying compounds within a complex matrix without prior knowledge of its chemical composition, is a promising technique for tobacco regulation, but it is not without challenges. The lack of standardized methods for sample generation, sample preparation, chromatographic separation, compound identification, and data analysis and reporting must be addressed so that the quality and reproducibility of the data generated by NTA can be benchmarked. This review discusses the challenges and highlights the opportunities of NTA in studying tobacco product constituents and emissions.

The sweet spot study-Developing e-liquid product standards for nicotine form and concentration to improve public health: Protocol for a randomized, double-blinded, crossover study.

OBJECTIVES: E-cigarettes pose significant risks to youth, but smokers may benefit from switching to e-cigarettes by reducing their exposure to toxicants, which creates a challenge for the Food and Drug Administration (FDA) in regulating e-cigarettes to protect population health. This study aims to develop e-liquid product standards for nicotine form and concentration that reduce the appeal of e-cigarettes to young people while keeping e-cigarettes available as a safer alternative for smokers. DESIGN AND PARTICIPANTS: A single-visit, double-blinded, randomized crossover design will be used to examine the effects of e-liquids with varying fractions of free-base nicotine (5%, 25%, 45%, 65%, 85%) among a sample of 66 young adult EC users and 66 older adult smokers, across ecologically valid total nicotine concentrations (20 mg or 50 mg/mL). INTERVENTIONS AND OUTCOMES: A 2-puff session will be conducted to test each of the 10 e-liquids in randomly assigned sequences, followed by a 10-minute washout period and participant ratings on appeal and sensory attributes such as throat hit and harshness, as well as behavioral intentions for continued use. Generalized linear mixed models will be used to determine a free-base nicotine level that has limited or no appeal to young adult e-cigarette users while remaining acceptable to smokers. CONCLUSIONS: This study will provide the FDA with scientific evidence regarding the effect of product standards that mandate a minimum threshold for the fraction of free-base nicotine. TRIAL REGISTRATION: The study is registered on clinicaltrials.gov under the identifier NCT05864586.

Nicotine flux as a powerful tool for regulating nicotine delivery from e-cigarettes: Protocol of two complimentary randomized crossover clinical trials.

INTRODUCTION: Electronic cigarette (EC) use has increased rapidly in the last decade, especially among youth. Regulating nicotine delivery from ECs could help curb youth uptake and leverage EC use in harm reduction yet is complicated by varying device and liquid variables that affect nicotine delivery. Nicotine flux, the nicotine emission rate, is a parameter that incorporates these variables and focuses on the performance rather than the design of an EC. Nicotine flux therefore could be a powerful regulatory tool if it is shown empirically to predict nicotine delivery and subjective effects related to dependence. METHODS AND ANALYSIS: This project consists of two complementary clinical trials. In Trial I, we will examine the relationship between nicotine flux and the rate and dose of nicotine delivery from ECs, hence, impacting abuse liability. It will also examine the extent to which this relationship is mediated by nicotine form (i.e., freebase versus protonated). At Yale School of Medicine (YSM), study participants will puff EC devices under conditions that differ by flux and form, while arterial blood is sampled in high time resolution. In Trial II, we will assess the relationship between nicotine flux, form, and subjective effects. At the American University of Beirut (AUB), participants will use EC devices with varying nicotine fluxes and forms, while dependency measures, such as the urge to use ECs, nicotine craving, and withdrawal symptoms, will be assessed. We will also monitor puffing intensity and real-time exposure to toxicants. ETHICS AND DISSEMINATION: The protocol of Trial I and Trial II was approved by YSM and AUB IRBs, respectively. We will disseminate study results through peer-reviewed publications and conference presentations. TRIAL REGISTRATION: NCT05706701 for Trial I and NCT05430334 for Trial II.

A Systematic Review of Analytical Methods for the Separation of Nicotine Enantiomers and Evaluation of Nicotine Sources.

The introduction of synthetic nicotine by the tobacco industry, also promoted as tobacco-free nicotine, presented new challenges for analytical chemists working in tobacco regulatory science to develop and optimize new methods to assess new nicotine parameters, namely enantiomer ratio and source. We conducted a systematic literature review of the available analytical methods to detect the nicotine enantiomer ratio and the source of nicotine using PubMed and Web of Science databases. Methods to detect nicotine enantiomers included polarimetry, nuclear magnetic resonance, and gas and liquid chromatography. We also covered methods developed to detect the source of nicotine either indirectly via determining the nicotine enantiomer ratio or the detection of tobacco-specific impurities or directly using the isotope ratio enrichment analysis by nuclear magnetic resonance (site-specific natural isotope fractionation and site-specific peak intensity ratio) or accelerated mass spectrometry. This review presents an accessible summary of all these analytical methods.

Carbonyl Emissions and Heating Temperatures across 75 Nominally Identical Electronic Nicotine Delivery System Products: Do Manufacturing Variations Drive Pulmonary Toxicant Exposure?

Studies of factors that impact electronic nicotine delivery systems (ENDSs) carbonyl compound (CC) emissions have been hampered by wide within-condition variability. In this study, we examined whether this variability may be related to heating coil temperature variations stemming from manufacturing differences. We determined the mean peak temperature rise (ΔTmax) and CC emissions from 75 Subox ENDSs powered at 30 W. We found that ΔTmax and CC emissions varied widely, with greater ΔTmax resulting in exponentially higher CC emissions. Also, 12% of atomizers accounted for 85% of total formaldehyde emissions. These findings suggest that major reductions in toxicant exposure might be achieved through regulations focusing on limiting coil temperature.

Impact of smoking intensity and device cleaning on IQOS emissions: comparison with an array of cigarettes.

SIGNIFICANCE: IQOS is a heated tobacco product that has been widely advertised by Philip Morris International (PMI) as a reduced-exposure product compared with cigarettes. Reduced exposure results from reduced emission of toxicants which could be influenced by product constituents and user behaviour. This study aims to assess the influence of user behaviour, including device cleaning and puffing parameters, on toxicant emissions from IQOS. METHODS: IQOS aerosols were generated by a smoking machine using the combination of two cleaning protocols (after 1 stick vs 20 sticks) and five puffing regimes (including standard cigarette puffing regimes and IQOS-tailored regimes). The generated aerosols were analysed by targeted methods for phenol and carbonyl quantification, and by chemical screening for the identification of unknown compounds. RESULTS: Puffing parameters significantly affected phenol and carbonyl emissions while device cleaning had no effect. Harsher puffing conditions like more, longer, and larger puffs yielded higher levels for most toxicant emissions. Comparing the obtained data with data reported by PMI on 50 cigarette brands smoked under different puffing regimes showed various trends for phenol and carbonyl emissions, with IQOS emissions sometimes higher than cigarettes. Also, the chemical screening resulted in the tentative identification of ~100 compounds in the IQOS aerosols (most of limited toxicity data). CONCLUSION: This study showed that puffing parameters, but not device cleaning, have significant effects on carbonyl, phenol and other emissions. Data analysis highlighted the importance of comparing IQOS emissions with an array of commercial cigarettes tested under different puffing regimes before accepting reduced exposure claims.

Assessing toxicant emissions from e-liquids with DIY additives used in response to a potential flavour ban in e-cigarettes.

SIGNIFICANCE: Electronic cigarettes (e-cigarettes) aerosolise liquids that contain nicotine, propylene glycol, glycerol and appealing flavours. In the USA, regulations have limited the availability of flavoured e-cigarettes in pod-based systems, and further tightening is expected. In response, some e-cigarette users may attempt to make their e-liquids (do-it-yourself, DIY). This study examined toxicant emissions from several aerosolised DIY e-liquids. METHODS: DIY additives were identified by reviewing users' responses to a hypothetical flavour ban, e-cigarette internet forums and DIY mixing internet websites. They include essential oils, cannabidiol, sucralose and ethyl maltol. E-liquids with varying concentrations and combinations of additives and tobacco and menthol flavours were prepared and were used to assess reactive oxygen species (ROS), carbonyl and phenol emissions in machine-generated aerosols. RESULTS: Data showed that adding DIY additives to unflavoured, menthol-flavoured or tobacco-flavoured e-liquids increases toxicant emissions to levels comparable with those from commercial flavoured e-liquids. Varying additive concentrations in e-liquids did not have a consistently significant effect on the tested emissions, yet increasing power yielded significantly higher ROS, carbonyl and phenol emissions for the same additive concentration. Adding nicotine to DIY e-liquids with sucralose yielded increase in some emissions and decrease in others, with freebase nicotine-containing e-liquid giving higher ROS emissions than that with nicotine salt. CONCLUSION: This study showed that DIY additives can impact aerosol toxicant emissions from e-cigarettes and should be considered by policymakers when restricting commercially available flavoured e-liquids.

Did JUUL alter the content of menthol pods in response to US FDA flavour enforcement policy?

BACKGROUND: The JUUL electronic cigarette (e-cigarette) remains popular in the USA and has a big prevalence among youth. In response to the popularity of JUUL and similar devices among youth, the US Food and Drug Administration issued in February 2020 an enforcement policy to remove all flavoured cartridge/pod-based e-cigarettes from the market except for tobacco and menthol. Subsequent studies showed that some users of the now-removed flavoured JUUL pods (especially cool mint) switched to menthol-flavoured JUUL pods with similar satisfaction. METHODS: We quantified menthol, nicotine, propylene glycol (PG) and vegetable glycerol (VG) in JUUL pod samples (Menthol, Classic Menthol and Cool Mint) that were purchased in 2017, 2018 and 2020 (only Menthol) to evaluate composition differences before and after the enforcement policy. We also analysed the samples to detect other cooling agents using a screening gas chromatography-mass spectrometry headspace method that we developed for this purpose. RESULTS: Menthol concentration was significantly higher in 2020 products than in products from prior years. Moreover, other cooling agents varied across pods. The PG/VG volume ratio was 27/63 in all pods examined. CONCLUSION: This study highlights how regulations intended to reduce e-cigarette prevalence among youth may influence changes in tobacco product characteristics in ways that regulators may not have foreseen.

Emerging ENDS products and challenges in tobacco control toxicity research.

Electronic nicotine delivery systems (ENDS) continue to rapidly evolve. Current products pose unique challenges and opportunities for researchers and regulators. This commentary aims to highlight research gaps, particularly in toxicity research, and provide guidance on priority research questions for the tobacco regulatory community. Disposable flavoured ENDS have become the most popular device class among youth and may contain higher nicotine levels than JUUL devices. They also exhibit enhanced harmful and potentially harmful constituents production, contain elevated levels of synthetic coolants and pose environmental concerns. Synthetic nicotine and flavour capsules are innovations that have recently enabled the circumvention of Food and Drug Administration oversight. Coil-less ENDS offer the promise of delivering fewer toxicants due to the absence of heating coils, but initial studies show that these products exhibit similar toxicological profiles compared with JUULs. Each of these topic areas requires further research to understand and mitigate their impact on human health, especially their risks to young users.

Analysis of mainstream emissions, secondhand emissions and the environmental impact of IQOS waste: a systematic review on IQOS that accounts for data source.

OBJECTIVE: To highlight the general features of IQOS literature focusing on the chemical analysis of IQOS emissions. DATA SOURCES: PubMed, Web of Science and Scopus databases were searched on 8 November 2021 using the terms 'heated tobacco product', 'heat-not-burn', 'IQOS' and 'tobacco heating system' with time restriction (2010-2021). The search yielded 5480 records. STUDY SELECTION: Relevant publications on topics related to IQOS assessment were retrieved (n=341). Two reviewers worked separately and reached agreement by consensus. DATA EXTRACTION: Data on author affiliation and funding, article type and date of publication were extracted. Publications were categorised depending on their focus and outcomes. Data on IQOS emissions from the chemical analysis category were extracted. DATA SYNTHESIS: Of the included publications, 25% were published by Philip Morris International (PMI) affiliates or PMI-funded studies. PMI-sponsored publications on emissions, toxicology assessments and health effects were comparable in number to those reported by independent research, in contrast to publications on IQOS use, market trends and regulation. Data on nicotine yield, carbonyl emissions, other mainstream emissions, secondhand emissions and IQOS waste were compared between data sources to highlight agreement or disagreement between PMI-sponsored and independent research. CONCLUSIONS: Our analysis showed agreement between the data sources on nicotine yield from IQOS under the same puffing conditions. Also, both sources agreed that IQOS emits significantly reduced levels of some emissions compared with combustible cigarettes. However, independent studies and examination of PMI's data showed significant increases in other emissions from and beyond the Food and Drug Administration's harmful and potentially harmful constituents list.

Electrical features, liquid composition and toxicant emissions from 'pod-mod'-like disposable electronic cigarettes.

INTRODUCTION: Use of flavoured pod-mod-like disposable electronic cigarettes (e-cigarettes) has grown rapidly, particularly among cost-sensitive youth and young adults. To date, little is known about their design characteristics and toxicant emissions. In this study, we analysed the electrical and chemical characteristics and nicotine and pulmonary toxicant emission profiles of five commonly available flavoured disposable e-cigarettes and compared these data with those of a JUUL, a cartridge-based e-cigarette device that pod-mod-like disposables emulate in size and shape. METHODS: Device construction, electrical power and liquid composition were determined. Machine-generated aerosol emissions including particulate matter, nicotine, carbonyl compounds and heavy metals were also measured. Liquid and aerosol composition were measured by high-performance liquid chromatography, gas chromatography-mass spectrometry/flame ionisation detection, and inductively coupled plasma mass spectrometry. RESULTS: We found that unlike JUUL, disposable devices did not incorporate a microcontroller to regulate electrical power to the heating coil. Quality of construction varied widely. Disposable e-cigarette power ranged between 5 and 9 W and liquid nicotine concentration ranged between 53 and 85 mg/mL (~95% in the protonated form). In 15 puffs, total nicotine yield for the disposables ranged between 1.6 and 6.7 mg, total carbonyls ranged between 28 and 138 µg, and total metals ranged between 1084 and 5804 ng. JUUL emissions were near the floors of all of these ranges. CONCLUSIONS: Disposable e-cigarettes are designed with high nicotine concentration liquids and are capable of emitting much higher nicotine and carbonyl species relative to rechargeable look-alike e-cigarettes. These differences are likely due to the lower quality in construction, unreliable labelling and lack of temperature control regulation that limits the power during operation. From a public health perspective, regulating these devices is important to limit user exposure to carbonyls and nicotine, particularly because these devices are popular with youth and young adults.

JUUL 'new technology' pods exhibit greater electrical power and nicotine output than previous devices.

In 2019, JUUL Labs began marketing in the European Union 'new technology' pods that incorporated a new wick that it claimed provided 'more satisfaction'. In this study, we compared design and materials of construction, electrical characteristics, liquid composition and nicotine and carbonyl emissions of new technology JUUL pods to their predecessors. Consistent with manufacturer's claims, we found that the new pods incorporated a different wicking material. However, we also found that the new pod design resulted in 50% greater nicotine emissions per puff than its predecessor, despite exhibiting unchanged liquid composition, device geometry and heating coil resistance. We found that when connected to the new technology pods, the JUUL power unit delivered a more consistent voltage to the heating coil. This behaviour suggests that the new coil-wick system resulted in better surface contact between the liquid and the temperature-regulated heating coil. Total carbonyl emissions did not differ across pod generations. That nicotine yields can be greatly altered with a simple substitution of wick material underscores the fragility of regulatory approaches that centre on product design rather than product performance specifications.

Might limiting liquid nicotine concentration result in more toxic electronic cigarette aerosols?

Some jurisdictions have instituted limits on electronic cigarette (ECIG) liquid nicotine concentration, in an effort to control ECIG nicotine yield, and others are considering following suit. Because ECIG nicotine yield is proportional to the product of liquid nicotine concentration (milligram per millilitre) and device power (watts) regulations that limit liquid nicotine concentration may drive users to adopt higher wattage devices to obtain a desired nicotine yield. In this study we investigated, under various hypothetical regulatory limits on ECIG liquid nicotine concentration, a scenario in which a user of a common ECIG device (SMOK TF-N2) seeks to obtain in 15 puffs the nicotine emissions equivalent to one combustible cigarette (ie, 1.8 mg). We measured total aerosol and carbonyl compound (CC) yields in 15 puffs as a function of power (15-80 W) while all else was held constant. The estimated nicotine concentration needed to achieve combustible cigarette-like nicotine yield at each power level was then computed based on the measured liquid consumption. We found that for a constant nicotine yield of 1.8 mg, reducing the liquid nicotine concentration resulted in greater amount of liquid aerosolised (p<0.01) and greater CC emissions (p<0.05). Thus, if users seek a given nicotine yield, regulatory limits on nicotine concentration may have the unintended consequence of increasing exposure to aerosol and respiratory toxicants. This outcome demonstrates that attempting to control ECIG nicotine yield by regulating one factor at a time may have unintended health effects and highlights the need to consider multiple factors and outcomes simultaneously when designing regulations.