NIH – Electronic Nicotine Delivery Systems (ENDS): Basic Mechanisms of Health Effects (R01, R21 – Clinical Trial Not Allowed)

September 15, 2017 by School of Medicine Webmaster

The following description was taken from the R01 version of this FOA.

Electronic Nicotine Delivery Systems (ENDS) are battery powered inhalation devices designed to deliver to the user an aerosol typically containing nicotine.  Since their introduction into the U.S nearly a decade ago, the prevalence of ENDS has increased rapidly. In 2013-2014, 5.5% of the adult population were current users, representing over 13 million people. In addition, past month use of ENDS among adolescents exceeded combustible cigarettes in 2015, 2016, and 2017.

ENDS are a complex class of devices.  A broad nomenclature is used to describe them, including e-cigarette, e-hookah, and vape pen. Their designs vary, from disposables that look like combustible cigarettes, to devices with rechargeable batteries and refillable tanks, and those with a box-shaped format that allow user control over aspects of the liquid aerosolization, such as the voltage supplied to the heating element. For the purposes of this FOA, the entire class of products are referred to as ENDS.

There is limited information on the safety of the devices and the aerosols they generate, how changes in the devices or aerosols affect nicotine delivery, or how the modulation of these aspects affect biological systems and behavior. ENDS aerosols have begun to be characterized for individual constituents, but further data is needed regarding how the constituents are generated and what risks may be associated with the extent of exposure to individual users. For example, while many of the flavorants used in the e-liquids are approved for use in foods, there is incomplete information on their effects when inhaled. These gaps in our understanding around ENDS indicate the need for further investigation at the molecular, cellular, physiological and behavioral levels to increase our understanding of the potential risks and benefits of ENDS use.

Program Scope and Research Objectives

This funding announcement encourages research evaluating the biological mechanisms whereby ENDS aerosols affect the normal and disease states relevant to human cells, tissues or organs. Studies of interest include understanding the characteristics of ENDS aerosols and how they are generated. Also of interest is how ENDS-specific constituents alter molecular, cellular and physiological pathways important in maintaining normal homeostatic functions or progression to disease states. Studies should make use of human cells or specimens, and where appropriate, can utilize cell or animal models that are relevant to humans and well justified. Applications should focus on constituents or aerosols unique to ENDS products; studies examining ENDS components that have been well-studied in other tobacco products or other health contexts are not high priority unless there is a unique aspect to ENDS exposure. Consideration should be given to the development of biomarkers that reflect exposure to ENDS aerosol and could provide information on the risks or benefits of exposure. Research areas of interest for participating NIH institutes are listed below.

Where appropriate, the standardized research e-cigarette ( should be considered for use in addressing specific research questions, or as a comparator for commercially available ENDS.

National Cancer Institute.  NCI encourages submission of applications designed to fill gaps in the knowledge base regarding mechanisms of toxicity and carcinogenicity of ENDS.  Examples of specific topics of interest to NCI include but are not limited to:

  • Effects of ENDS aerosols on carcinogenesis and tumor progression;
  • Effects of ENDS exposure on the response or resistance to targeted, radiation, or chemo therapies;
  • Consequences of ENDS aerosol exposure in relevant animal models of cancer;
  • Cellular and molecular mechanisms of carcinogenicity by exposure to ENDS aerosols; and
  • Identification and validation of specific molecular markers of ENDS exposure or toxicity.

National Institute of Dental and Craniofacial Research.  NIDCR is interested in all applications that are relevant to the NIDCR mission and strategic plan.  Potential applicants are encouraged to speak with a NIDCR program official to discuss the relevance of proposed research topic(s).  Applications that propose to prove causal pathways between ENDS (specifically e-cigarettes) and dental, oral, and/or craniofacial diseases and conditions are of higher priority.  Those applications that demonstrate correlations are of lower priority.  NIDCR supports research that examines the basic mechanisms of effects in pre-clinical investigations.

For additional information on the NIDCR mission and strategic plan please see the NIDCR website:

NIDCR is interested in investigations that include but are not limited to:

  • Determination of the synergistic biological effects of e-cigarette aerosol mixtures on cells, tissues and organs of the oral cavity using appropriate in vitro and in vivo model systems,
  • Analysis of genotoxicity/DNA damage, cellular metabolism, mutagenicity, and/or transformation potential, effects on cell proliferation and cell death, of e-cigarette aerosol mixtures using appropriate in vitro and/or in vivo model systems with an emphasis on oral and periodontal epithelial cells,
  • High throughput analysis (e.g. genomic, epigenomic and proteomic analyses) to understand the biological and physiological effects of e-cigarette aerosols on cells, tissues and organs of the oral cavity,
  • Examination and comparison of the effects on oral and/or periodontal epithelial cells in chronic users of e-cigarettes, smokers of combustible cigarettes and non-smokers,
  • Analysis of effects of e-cigarettes on factors responsible for the maintenance of oral homeostasis such as cytokine production and downstream signaling pathways, immune cell function, and oral microbiome, and
  • Assessment of effects of e-cigarettes on salivary gland function, saliva flow; and on dental/periodontal health using appropriate in vivo model systems.

National Institute on Drug Abuse.  NIDA is interested in supporting pre-clinical and clinical research that examines the basic mechanisms of effects by ENDS as they relate to addiction.  Investigations that explore the interaction between genetics or epigenetics and ENDS are of interest. The Institute also encourages research on the effects of ENDS flavoring via in vitro or in vivo investigations.  Further, NIDA is interested in investigations that explore neuronal mechanisms, such as function of neurons, astrocytes, microglia or brain circuitry, associated with the use of ENDS and exposure to the aerosol constituents. How sex differences might impact the effects of ENDS are also of interest. Potential applicants are advised to speak with a NIDA program official to discuss the relevance and priority to NIDA of potential research topic(s). NIDA is interested in studies that include but are not limited to:

  • Behavioral or cognitive processes (e.g., learning, memory, emotion), and their neurobiological mechanisms, as variables contributing to ENDS initiation, escalation, maintenance, abstinence, or relapse;
  • Characterization of transition points and stages in the development of an SUD to ENDS, including the use of biomarkers or other neurobiological signatures that predict transition to more compulsive patterns of intake;
  • Effects of genetics/epigenetics on ENDS use and addiction;
  • Assessments of transcriptomic-, proteomic-, or metabolomic profiles either in vitro or in vivo associated with ENDS exposure, including effects by flavorings.

National Institute on Environmental Health Sciences.  NIEHS is most interested in supporting research that examines basic mechanisms of effects related to substances used in ENDS.  NIEHS seeks to support studies that examine potential relationships between ENDS flavorings and exposure to toxicants.  The Institute is also interested in studies that examine the relationship between secondary and tertiary ENDS vapor exposures and genetic and physiological outcomes.  NIEHS invites applications that include but are not limited to:

  • Identifying relationships between individual flavored/non-flavored constituents and specific measures of toxicity,
  • Identifying the flavored /non-flavored constituents of second hand and tertiary e-cigarette vapors linked to known toxic effects,
  • Evaluating health effects associated with toxic second hand/tertiary e-cigarette vapors,
  • Evaluating the air quality in homes where e-cigarettes are used,
  • Identifying or discover pediatric adverse health issues associated with toxic second hand/tertiary e-cigarette vapor exposures,
  • Identifying cardio-pulmonary dysfunction(s) associated with toxic second hand/tertiary e-cigarette vapor exposures,
  • Analyzing of epigenetic reprogramming as a consequence of toxic second hand/tertiary e-cigarette vapor exposures, and
  • Analyzing of gene expression profile associated with toxic second hand/tertiary e-cigarette vapor exposures.

Deadlines:  November 27, 2017; June 27, 2018; October 24, 2018; June 27, 2019; October 24, 2019; June 27, 2020


R01 –

R21 –

Filed Under: Funding Opportunities