Year 4 Pilot Projects
Title:Dopaminergic regulation of flavor in e-cigarette: A study into the addictive potential of flavor (PP15Y4)
Investigator(s): Mauricio Rangel-Gomez, Ph.D., University of Maryland
Abstract: The Surgeon General of the United States, in his 2016 e-cigarette report, has indicated that e-cigarette use increased by 900% in the youth population (School students) between 2011 and 2015. Such report also suggests that the effects of certain constituents of e-cigarette liquids, particularly flavorants, are an important knowledge gap . The proposed project approaches this identified research gap from the neurobiology of addiction, with emphasis on the effects of the flavorants added to e-cigarettes. Concerning the neurobiology of addiction, dopamine (DA) has been largely identified as the main neural mediator of the initiation and continuation of the consumption of substances of abuse. Nicotine causes dopamine release, which explains the addictive qualities of this substance. In combustible tobacco, the addition of flavorants has been controlled, but it is not the case for e-cigarettes. This pilot project aims to determine, by means of a dopaminergic pharmacological challenge, the capabilities of flavor to generate an effect in the dopaminergic system. E-cigarette consumers will be recruited from the community. The participants will attend two sessions in a crossover placebo-controlled experiment; each session will consist of 6 cross-balanced vaping moments (3 with flavored fluid, 3 with unflavored fluid), at different times after the administration of a dopaminergic agonist or placebo. This manipulation will allow to follow the temporal progression of the dopaminergic manipulation, and to determine how flavor and nicotine effects are influenced by different levels of dopaminergic activity. The interactions between nicotine, flavor and dopamine will be inspected by means of event related potentials(ERPs), and the electrophysiological activity at different frequency bands. This electrophysiological activity will be recorded while participants perform four different tasks (resting state, go/no-go, gambling and delay reward), which have been proven to be related to the action of the dopaminergic circuitries. If there is an interaction between flavor and enhanced dopaminergic activity, it can be argued that flavor has an effect in the dopaminergic function, thus it has addictive potential via DA action. Therapy, and reduced nicotine cigarettes; and (3) develop and test the effectiveness of intervention messages that aim at addressing these misperceptions. Findings from the current study will identify the knowledge gap between the general public and the scientific community and inform the FDA about potential communication strategies to improve smokers’ understanding of nicotine products.
Title:Addressing Nicotine Misperceptions (PP14Y4)
Investigator(s): Rui Shi, Ph.D., University of Maryland
Abstract: A large proportion of smokers as well as non-smokers have misperceptions of the health risks associated with nicotine use. Some people believe nicotine is completely safe and harmless while some other people see nicotine as the main carcinogen in cigarettes and the leading cause of diseases (e.g. lung cancer and heart attack). Both the underestimation and the overestimation of nicotine harm could be consequential to various sectors of the smoking population. On the one hand, the belief in nicotine safety may lead electronic cigarette users to ignore the risk associated with their use of e-cigarettes. On the other hand, for smokers who are trying to quit, belief in exaggerated harm of nicotine could deter them from using nicotine replacement therapy (NRT) as a quitting aid. Elevated harm perception could also lead smokers to believe that reduced nicotine cigarettes are healthier. Although there are no RNC on the market, if the agency ever decides to regulate nicotine level in cigarettes this study can inform FDA how to communicate the policy change to avoid misperception. This project will (1) examine smokers’ existing misperceptions of the health risks associated with nicotine use and identify demographic and behavioral characteristics associated with the misperceptions; (2) explore the association between smokers’ nicotine perception and their attitude / intention / past use of three nicotine products, namely electronic cigarette, nicotine replacement therapy, and reduced nicotine cigarettes; and (3) develop and test the effectiveness of intervention messages that aim at addressing these misperceptions. Findings from the current study will identify the knowledge gap between the general public and the scientific community and inform the FDA about potential communication strategies to improve smokers’ understanding of nicotine products.
Title:Exhaled Breath Microbiome of Smokers and Non-smokers (PP13Y4)
Investigator(s): Somayeh Youssefi, Ph.D., University of Maryland
Abstract: Smoking can damage nearly every organ in the body and is recognized as a risk factor for various diseases including lung cancer, chronic obstructive pulmonary disease (COPD), stroke, heart attacks, influenza, asthma, and interstitial lung disease. It has been shown that there is a correlation between shifts in the lung microbiome and several pulmonary diseases, such as lung cancer and COPD. Very little is known about the microbiota of lungs due to the invasive nature of most sampling methods and the inefficiency of non-invasive exhaled breath collection using the popular exhaled breath condensate (EBC) method. We recently developed a new instrument with much improved capability to collect the human exhaled breath aerosol (EBA) generated by distal lung airways with funding from IARPA: the Human Exhaled Aerosol Droplet (HEAD) Sampler. This novel system far exceeds the efficiency of EBC systems and collects exhaled breath aerosols with near 100% efficiency on a very thin layer of ice, preserving labile molecules and avoiding losses due to incomplete extraction from impaction substrates. We were capable of collecting exhaled breath samples for proteomics and miRNA analysis. We also recently collected pilot samples for microbiome analysis. We plan to use our new collection device to collect exhaled breath aerosols and study the lung microbiota of smokers and compare the results with lung microbiota of healthy individuals. We will recruit twenty participants to form two groups (smokers and non-smokers) and will collect exhaled breath samples as well as saliva, buccal and appropriate background samples to ensure that EBA samples are not contaminated and that our findings truly represent lung microbiota. This project will increase our broad understanding of the lung microbiome and can help us find techniques for early detection of potential smoking-related health problems.
Year 3 Pilot Projects
Title:Detection and Identification of Chemicals from Tobacco Smoke in Airway Surface Liquid (PP12Y3)
Investigator(s): Erich D. Strozier, Ph.D., Battelle
Abstract: The objective of this proposed developmental pilot study is to develop analytical methods to detect and identify chemicals in airway surface liquid after exposure to tobacco smoke. Airway surface liquid is a critical interface affecting human exposure to the toxic smoke from a tobacco product. The methods to be developed in the proposed pilot study are intended for use with airway surface liquid samples exposed to tobacco smoke in vitro. This pilot study includes an inter-TCORS collaboration with Drs. Rob Tarran and Arunava Ghosh of the University of North Carolina Medical School (UNC) TCORS. We will receive de-identified, coded and exposed airway surface liquid samples from UNC, and these samples will be analyzed at Battelle. Identifying the tobacco-related components detected in the exposed samples can provide valuable data on which of the thousands of chemicals from mainstream smoke are likely to be collected in a human smoker’s respiratory system. A sample of airway surface liquid will first be exposed in vitro to mainstream tobacco smoke. Aliquots of the exposed sample and a non-exposed sample, to be used as a control, will be analyzed utilizing powerful analytical chemistry techniques for detecting and identifying unknown chemicals in complex samples—specifically, liquid chromatography–quadrupole time-of-flight mass spectrometry (LC-QTOFMS) and two-dimensional gas chromatography–time-of-flight mass spectrometry (GC×GC-TOFMS). The deliverables for the proposed pilot study are analytical methods that can be routinely used in future research to detect tobacco-related chemicals in airway surface liquid samples. The study will be carried out to meet the following two aims: (1) Develop a method for analyzing exposed airway surface liquid samples using LC-QTOFMS and assess its reproducibility, and (2) Develop a method for analyzing exposed airway surface liquid samples using GC×GC-TOFMS and assess its reproducibility.
Title:Pilot study to detect aldehyde-DNA adducts and DNA-damage related gene expression following vaping (PP11Y3)
Investigator(s): Samera Hamad, Ph.D., University of Maryland
Abstract: The Family Smoking Prevention and Tobacco Control Act (TCA), grants the U.S. Food and Drug Administration (FDA) the authority to regulate the manufacture, marketing and distribution of tobacco products. Section 907(a) of the TCA allows FDA to develop product standards, including establishing upper limits for harmful and potentially harmful constituents (HPHCs) in tobacco and smoke to protect public health. The majority of the chemicals in FDA’s established list of HPHCs are human carcinogens. Newly regulated, the FDA considers e-cigarettes a tobacco product, and intends to assert authority to regulate this product. Early reports show that e-cigarettes deliver HPHCs, but the level of potential risk from these products has not yet been established. The objective of this pilot project is to identify and measure biomarkers (especially formaldehyde and acetaldehyde-DNA adducts) in human biological fluids (blood and buccal samples) after participants are exposed to incremental doses of volatile HPHCs from scripted (duration and number of puffs) e-cigarette vaping. Genes that are triggered from the incremental e-cigarette exposures will also be identified to gain a preliminary understanding of dose response, and the toxicity pathways that are activated by vaping e-cigarettes. The biological samples analyzed in this pilot will have been collected as part of an on-going study, in which continuous measurements in exhaled breath (from vaping different puff numbers) will be used to estimate body burn of volatile HPHCs. The biological samples will be analyzed for aldehyde-DNA adducts using mass spectrometry, and for gene expression using Reverse Transcription-Polymerase Chain Reaction (RT-PCR). Correlation matrix and regression models will be used to establish relationships between the levels of aldehyde-DNA adducts and the genes triggered from the incremental dose exposure to aldehydes. These data will further clarify the toxicity of e-cigarette emissions and inform a larger study that will more thoroughly define the relationship between exposure to VOCs from e-cigarettes and DNA damage.
Title: Fungal Constituents and Their Role in Tobacco-specific Nitrosamine and Mycotoxin Formation in Smoked and Smokeless Tobacco Products (PP10Y3)
Investigator(s): Eoghan Smyth, Ph.D., University of Maryland
Abstract: There is a lack of data regarding the fungal constituents of tobacco products, changes in fungal constituents that might occur during storage under various environmental conditions, and the role of these fungi in tobacco-related adverse health effects. Tobacco fungal constituents may play significant roles in the development of both infectious and chronic diseases among tobacco users, through the production of carcinogenic compounds, such as tobacco-specific nitrosamines (TSNAs), and mycotoxins. However, despite the potentially critical significance of tobacco fungal constituents, this field of tobacco research has been largely ignored. To address this knowledge gap, we will conduct time series experiments with five commercially-available smoked and smokeless tobacco products under three different environmental conditions. Using next generation sequencing we will characterize the fungal microbiome of these products, through DNA sequencing of the Internal Transcribed Spacer 1 (ITS1) region, a sequence located between the 18S and 5.8S rRNA genes in fungal genomes. We will also sequence the metatranscriptome to explore gene expression changes of the fungal microbiome through the course of the time series. In addition, we will measure changes in the chemical constituents of the tobacco products using LC-MS/MS to see changes in mycotoxin and TSNA levels during storage of these products. This project will increase our broad understanding of tobacco fungal constituents and their functional role in the production of TSNAs and mycotoxins during tobacco storage.
Title: Pilot study to inform a human model of incremental volatile HPHC exposure from electronic cigarette use for the assessment of boost biomarkers and development of product standards (PP9Y3)
Investigator(s): Marielle C. Brinkman, B.S., Battelle
Abstract: The electronic cigarette (e-cigarette) market has grown dramatically in recent years, particularly among adolescents and young adults. E-cigarette use in this population may play an important role in initiation and use of other nicotine-containing tobacco products. Given their widespread appeal, concern is growing over the safety of these products, as the emissions they produce under typical conditions of use have not been sufficiently evaluated for toxicity via the inhalation exposure route. During vaping the humectants (usually propylene glycol and/or vegetable glycerine) and other components of the e-liquid, e.g., nicotine and flavorants, are heated to high temperatures, which results in thermal conversion of these chemicals into harmful byproducts, including volatile organic compounds classified by FDA harmful and potentially harmful constituents (HPHCs) such as formaldehyde, acetaldehyde, acetone, and acrolein. The public health significance of these exposures has not been fully established, and current knowledge is insufficient to establish product standards and define potential rulemaking surrounding e-cigarettes. To begin to fill this knowledge gap, we have proposed a pilot study to determine the amount of e-cigarette use results in detectable levels of these volatile chemicals in exhaled breath and to determine the concentration and residence time of these chemicals in the body. We will also collect blood and buccal epithelium before, during and after e-cigarette use to be stored for future analysis. These measures will inform a larger study that will aim to determine the dose-response relationship for exposure to volatile HPHCs in e-cigarettes and the formation of adducts.
Title: Demonstration of Particle Size Segregated Chemical Analysis of the Aerosol Generated by Electronic Cigarette (PP8Y3)
Investigator(s): Vladimir B. Mikheev, Ph.D., Battelle
Abstract: This project will develop methods for size segregated collection and analysis of metal content of electronic cigarette aerosol. Aerosol size defines how particles are delivered and deposited in the human respiratory system, but there is a lack of reliable data on electronic cigarette aerosol size distribution. Preliminary data obtained using advanced real-time high resolution technique have shown that unlike combustible cigarettes, electronic cigarette aerosol contains high concentrations of nanoparticles. The toxicological impact of chemicals attached to nanoparticles might be higher than for the larger submicron particles typical of combustible cigarette smoke. Nanoparticles may efficiently deposit by diffusion in all regions of the respiratory tract, as their small size facilitates uptake into cells and transcytosis across epithelial cells into the blood and lymph circulation systems to reach potentially sensitive target sites such as bone marrow, lymph nodes, spleen, and heart. In general the greater surface area per unit mass of nanoparticles, compared with larger-sized particles of the same chemistry, renders nanoparticles more active biologically.The chemical content of e-cigarette nanoparticles is unknown, but preliminary results suggest they may be largely inorganic in nature. Chronic inhalation of metallic nanoparticles has been linked to adverse pulmonary and cardiovascular outcomes. There is a critical need to develop methods of size segregated sampling and inorganic analysis of e-cigarette aerosol. A combination of continuous real-time and discrete methods will be applied to monitor e-cigarette aerosol evolution during the puff and simultaneously collect size segregated samples. The levels of inorganic metals classified by the FDA as harmful and potential harmful constituents will be quantified in the two particles sizes (submicron and nanoparticles). This pilot study will examine a limited set of aerosol samples generated using one cig-alike and one tank-style e-cigarette, and focus on quantifying the target inorganic HPHCs and other metals in the submicron and nanoparticles. Results of this study will inform the design of a larger project that will examine a wider range of electronic cigarette devices and operating conditions to quantify a larger suite of toxic organic and inorganic compounds.
Year 2 Pilot Projects
Title: Development of Pilot Survey Questionnaire on Electronic Cigarette Use (PP3Y2)
Investigator(s): Hyoshin Kim, Ph.D., Battelle
Abstract: The objective of the proposed Pilot/Development Study is to develop and pretest a survey questionnaire that collects data to describe and classify types of electronic cigarette (e-cig) users based on their vaping behaviors. As part of the effort to better understand “vaping” behaviors for e-cigs, the proposed research team collected qualitative data from the focus groups and in-depth interviews for the TCORS Year 1 Pilot/Development Study. Those findings provided detail for the complex e-cig use behaviors currently being practiced by sole (e-cig only) and dual (e-cig and combustible) e-cig users. From collected data, the research team learned: What constitutes e-cig vaping; what constitutes typical nicotine dosage among typical e-cig users; what constitutes some e-cig users’ experience; and how e-cig users use e-cigs throughout the day and week (with and without concurrent use of combustible cigarettes). Furthermore, given the many new product characteristics available (e.g., various nicotine levels, adjustable battery power, and flavors), users are exploring a number of options not applicable to conventional cigarette smoking. A simple adoption of combustible cigarette smoking survey questionnaire questions to assess e-cig use is insufficient in order to provide accurate descriptions of how users use e-cigs, especially because currently available e-cig related measures do not necessarily account for a wide variety of e-cig product characteristics and product options. There is thus a need for a comprehensive questionnaire able to track e-cig use behavior taking into account a wide array of variable factors related to the use of e-cigs. The proposed pilot questionnaire will address the current need for assessment tools that can be used to estimate exposure to nicotine and other harmful constituents associated with e-cig use. The end product of this study, the Pilot Questionnaire, is a critical step in developing a validated survey questionnaire that can be used in population-based surveys in order to understand how a nationally-representative sample of the US population uses e-cigs and to estimate their total exposure to nicotine and toxins from e-cig use.
Title: Motivations, Patterns, and Antecedents of Dual Use of Little Cigars/Cigarillos and Cigarettes in a High Risk Population (PP4Y2)
Investigator(s): Erin L. Mead, Ph.D., University of Maryland, Robert Feldman, Ph.D., University of Maryland, Thomas Kirchner, Ph.D., New York University, Sarah Lindstrom Johnson, Ph.D., Arizona State University, James Butler, III, Dr.P.H., University of Maryland, and Rob Feldman, Ph.D., University of Maryland
Abstract: The 2009 Family Smoking Prevention and Tobacco Control Act gave the Food and Drug Administration (FDA) the authority to regulate the manufacture, distribution, and marketing of tobacco products to protect the public’s health. A proposed deeming rule currently under consideration at the FDA would extend its authority to include cigar products, including little cigars and cigarillos (LCCs). The FDA has called for further research on cigar use including multiple use with other tobacco products, perceptions, and dependence to assist in its regulation of cigar products. Current research has shown that the prevalence of LCC use and dual use of cigarettes and LCCs are increasing in the United States, particularly among African Americans and young adults, even as overall tobacco use has declined. Limited work has been done to understand and characterize the growing dual use of cigarettes and LCCs in this high risk, priority population. Using a transdisciplinary approach, the pilot study will use a sequential mixed methods design to explore motivations for dual use of LCCs and cigarettes (Aim 1) and to characterize naturalistic patterns of dual use and antecedents to cigarette and LCC smoking (Aims 2 & 3) among African American young adult (aged 18-29 years) dual users. Up to 125 participants will be enrolled. Data will be captured using concept mapping (Aim 1) and ecological momentary assessment (Aims 2 & 3). Such work is needed as a foundation for future research in regulatory science to inform FDA regulations of LCCs.
Title: A Comparison of One-Time Little Cigar and Cigarette Use in Exposure to Tobacco Smoke (PP5Y2)
Investigator(s): Babita Das, Ph.D., University of Maryland
Abstract: The 2009 Family Smoking Prevention and Tobacco Control Act grants the Food and Drug Administration (FDA) authority to regulate the sales of combustible tobacco products. Unlike cigarettes, little cigars are not restricted by regulations controlling taxation, flavors, or package size. Despite a recent tripling in U.S. little cigar sales, plus reports of smokers switching from cigarettes to little cigars or using both products, little is known about the behaviors involved in little cigar use. It remains unclear whether little cigar users inhale tobacco smoke like cigarette users, and whether distinct smoking patterns during little cigar and cigarette use lead to differing amounts of tobacco smoke exposure. Puff and inhalation behaviors serve as measures of tobacco smoke exposure. Comparing puff and inhalation behaviors from little cigar and cigarette use will address questions surrounding the inhalation behavior of little cigar users and differences in amount of smoke exposure between these two products. Smoking topography is a reliable method used to measure puff behavior, but no standard procedure exists to measure inhalation behavior in smokers. The proposed study aims to 1. introduce a novel shoulder rise method to measure and compare amount of inhalation during little cigar and cigarette use, 2. use smoking topography to measure and compare puff behavior associated with little cigar and cigarette use, and 3. measure acute subjective responses after one-time use of each product. In a within-subjects two-day cross-over trial, thirty cigarette smokers will each smoke one cigarette and one little cigar. The order of product exposure will be randomized. Findings will inform regulatory authority about how puff and inhalation behaviors during little cigar and cigarette use may contribute to risks of smoke exposure, plus support future work to distinguish tobacco and smoke constituents in little cigars from those in cigarettes, and compare risks of smoke exposure between single-product and multi-product tobacco smokers.
Title: Genomic Benchmark Dose Modeling for Tobacco Product Toxicity Thresholds (PP6Y2)
Investigator(s): Courtney A. Granville, Ph.D., M.S.P.H., DABT, and David Friedenberg Ph.D., Battelle
Abstract: The Family Smoking Prevention and Tobacco Control Act grants FDA the authority to regulate the manufacture, marketing, and distribution of tobacco products, including the authority to set tobacco product standards for the protection of public health. The original rule bans the presence of any constituent (including a smoke constituent) in cigarettes, including the tobacco, filter, paper, or other component parts that confers a characterizing artificial or natural flavor (other than tobacco or menthol) or an herb or spice. Additionally, the FDA Center for Tobacco Products (CTP) has the authority to amend current standards and propose new standards for the purpose of protecting public health. Theoretically, these standards could be extended beyond flavorings and other additives to other constituents of tobacco, including those considered harmful and potentially harmful constituents (HPHCs). The establishment of such standards will require a sound base of regulatory science (the science of developing new tools, standards and approaches to assess the safety, efficacy, quality and performance of FDA-regulated products) to inform these standards. One approach to establishing product standards is for CTP to limit additives, such as flavorings and enhancers of addictiveness to levels that do not increase product toxicity through the establishment of a benchmark dose (BMD) for the constituent or additive in question. A BMD is a statistical lower confidence limit for a dose that produces a predetermined change in response rate of an adverse effect (called the benchmark response or BMR) compared to background and is determined using mathematical models. The purpose of this pilot study is to determine the utility of a genomic benchmark dose approach to defining toxicity thresholds for new or modified tobacco products such as low and ultra-low tar cigarettes with a goal of extending the model to additives such as menthol and other flavorings. The results will be derived using freely available genomic profiles and software for benchmark dose modeling.
Title: Cognitive, Affective, and Neurophysiological Processes Underlying Nicotine Withdrawal and Satiation (PP7Y2)
Investigator(s): Debra Bernat, Ph.D., University of Maryland, Edward Bernat, Ph.D., University of Maryland
Abstract: The primary goal of this study is to develop and validate a comprehensive neurophysiological battery and associated analytic framework to index primary neurobiological processes underlying the withdrawal and satiation cycle at the core of nicotine addiction. Data from 50 e-cigarette users will be collected. A within subject pre-post design will be used to assess the pre-consumption (e.g. withdrawal) and post-consumption (e.g. satiation) process using advanced EEG time-frequency energy and phase-synchrony approaches to index regional brain activation and functional connectivity. The neurophysiological battery is specifically designed to index salience and control brain systems, an emerging cognitive-neuroscience framework for understanding cognition, affect, and goal-directed behavior. This comprehensive framework will provide a new level of detailed information that can be used to assess differential addictive properties of current and emerging nicotine products.
Year 1 Pilot Projects
Title: Development of Electronic Cigarette Use Scale through Qualitative Data Collection (PP1Y1)
Investigator(s): Hyoshin Kim, Ph.D., Battelle and Brian Flaherty, Ph.D., University of Washington
Abstract: The proposed pilot study is designed to address the current data gap surrounding appropriate and meaningful measures of electronic cigarette (e- cigarette) use and the associated nicotine dependence. The field of public health was caught off guard by the sudden popularity of e-cigarettes. To date, no data are available to compare cigarette smoking to “vaping” behaviors for e-cigarettes. Furthermore, there is an urgent need for revising the currently available questionnaires to accurately identify the level of nicotine dependence for e-cigarette users. Until scientific consensus emerges in proposing and validating an equivalence scale, tobacco researchers are left to merely guess as to how best to use the current tobacco use measures. Data is needed to achieve this consensus. By collecting focus group data from e-cigarette users who were previous cigarette smokers, or are currently using both cigarettes and e-cigarettes, the proposed team will attempt to explore the similarities and differences between user behaviors and experiences in both combustible cigarettes and e-cigarettes. These data will inform how current combustible tobacco use measurement tools can be modified for use with e-cigarette users. Study objectives include gaining a better understanding of what constitutes smoking or vaping e-cigarettes; what constitutes a standard dosage among typical e-cigarette users; and how e-cigarette users use e-cigarettes temporally throughout the day and week, and with and without concurrent use of combustible cigarettes. These results will be used to inform the study design for a larger study, with the goal of developing and revising current nicotine delivery device use measures in the field.
Title: Potential New or Distinctive Exposures from Little Cigars (PP2Y1)
Investigator(s): Theodore Klupinski, Ph.D., Battelle
Abstract: Characterizing flavors other than menthol have been banned in the USA for use in cigarettes but not in little cigars, and it is known that young people smoke flavored little cigars in substantial amounts. This work demonstrates an approach that can be used to identify potential new or distinctive chemical exposures associated with little cigars, including flavored little cigars. Mainstream smoke samples will be machine-generated from several different little cigar products and several different cigarette products. Organic components will be extracted from the total particulate matter collected from the mainstream smoke, and the extracts will be analyzed using two-dimensional gas chromatography with time-of-flight mass spectrometry (GC×GC-TOFMS) to determine specific chemical compounds present. Data will be compared to determine differences between the little cigar samples and the cigarette samples. A “new exposure” would be indicated by a compound detected in little cigar smoke but not in cigarette smoke. A “distinctive exposure” would be indicated by a compound detected in both little cigar smoke and cigarette smoke, but at substantially higher concentrations in little cigar smoke. The data obtained from this study and, more generally, the applied analytical technique can contribute to the science base that the Food and Drug Administration (FDA) Center for Tobacco Products (CTP) may need when considering the established list of harmful and potentially harmful constituents (HPHCs) in tobacco products and tobacco smoke.