Investigative analysis of blood–brain barrier penetrating potential of electronic nicotine delivery systems (e-cigarettes) chemicals using predictive computational models

ABSTRACT

Introduction

Seizures are known potential side effects of nicotine toxicity and have been reported in electronic nicotine delivery systems (ENDS, e-cigarettes) users, with the majority involving youth or young adults.

Areas Covered

Using chemoinformatic computational models, chemicals (including flavors) documented to be present in ENDS were compared to known neuroactive compounds to predict the blood–brain barrier (BBB) penetration potential, central nervous system (CNS) activity, and their structural similarities. The literature search used PubMed/Google Scholar, through September 2023, to identify individual chemicals in ENDS and neuroactive compounds.

The results show that ENDS chemicals in this study contain >60% structural similarity to neuroactive compounds based on chemical fingerprint similarity analyses. The majority of ENDS chemicals we studied were predicted to cross the BBB, with approximately 60% confidence, and were also predicted to have CNS activity; those not predicted to passively diffuse through the BBB may be actively transported through the BBB to elicit CNS impacts, although it is currently unknown.

Expert Opinion

In lieu of in vitro and in vivo testing, this study screens ENDS chemicals for potential CNS activity and predicts BBB penetration potential using computer-based models, allowing for prioritization for further study and potential early identification of CNS toxicity.

KEYWORDS:

• Blood–brain barrier
• central nervous system activity
• electronic cigarettes (e-cigarettes)
• electronic nicotine delivery systems (ENDS)
• tobacco products
• E-cigarette or vaping product use-associated lung injury (EVALI)
• neurotoxicity
• vaping

Article highlights

• It is currently unknown if the chemicals in electronic nicotine delivery systems (ENDS) can penetrate the blood–brain barrier or have central nervous system impacts.

• The physiochemical properties of chemicals in ENDS and neuroactive compounds were investigated and compared using computational modeling approaches.

• This study predicted that many of the chemicals in ENDS may penetrate the blood–brain barrier and have neurological effects.

• This computational analysis is significant because it adds chemicals in ENDS to the body of evidence regarding potential CNS activity.

• This tiered approach using new approach methodologies (NAMs) is useful in predicting the BBB penetration potential and CNS activity to aid in decision-making on the neuroactive potential of chemicals in ENDS.

Declaration of interest

K Stratford, J Kang, Z Tu, and L Valerio are employees of the FDA, Center for Tobacco Products, Office of Science, Division of Nonclinical Science. Although the author is an FDA/CTP employee, this work was not done as part of his/her official duties. The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Food and Drug Administration. S Healy is an employee of the EPA. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Data availability statement

The full dataset for the present study is available in Supplementary Table 2.

Author contributions

K Stratford and L Valerio conceived and designed the research; K Stratford completed the analysis; K Stratford, J Kang, S Healy, and L Valerio completed the interpretation of the data; K Stratford wrote the initial draft of the manuscript; K Stratford, J Kang, S Healy, Z Tu, and L Valerio revised the manuscript.

Acknowledgments

This work entitled “Preliminary Investigative Analysis of Flavor Compounds Crossing Blood‐Brain Barrier Using Computational Models” was previously accepted for a poster presentation at the 59^th Annual Society of Toxicology (SOT) Meeting in March 2020. However, the meeting was canceled due to the unprecedented emergence of the COVID-19 pandemic. The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Food and Drug Administration or the Environmental Protection Agency.

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/17425255.2024.2366385

Additional information

Funding

This paper was not funded.