In response to Morgan and Jones, consumption of e-liquids in volumes of >10 mL/day is not uncommon, especially for users tapering down nicotine strength. Users of low nicotine strength (3–6 mg/mL) e-cigarette liquids often vape more frequently to compensate for low nicotine concentrations, some consuming large e-liquid volumes in the range of 15–30 mL/day.2 Surveys of vape shop customers found that users vaping low nicotine e-liquids (average of 3.3 mg/mL) consumed an average of 9 mL/day (ranging between 1.7–17.7 mL/day) and a substantial portion (13%) of these low nicotine users frequently used mint/menthol e-cigarette liquids.3 Other surveys corroborate high volume consumption (> 10 mL per day) in large proportions of users of low nicotine strength.3,4 These high volume consumers predominantly use sub-ohm devices..
Morgan and Jones calculated a wider but still concerning safety margin for pulegone in e-cigarettes using the No Observed Adverse Effect Level (NOAEL) of 37.5 mg/kg bw/day determined by the European Medical Agency (EMA).5 Our risk analysis was based on US FDA’s NOAEL of 13.39 mg/kg bw/day, derived from carcinogenicity studies in rodents.6 The FDA is required by law to prioritize regulatory decisions based on food additive carcinogenicity; we therefore used FDA’s NOAEL.
In contrast, the European NOAEL is based on the assessment of pulegone’s liver and kidney toxicity.5 Margin of Exposure (MOE) calculations for non-cancer organ toxicity can vary across regulatory agencies and depend on the chemical nature, metabolism, organ distribution, species scaling and applicable uncertainty factors of the toxicant. The resulting risk levels for pulegone were not within the scope of our study focusing on carcinogenicity, and hence not analyzed. Our risk analysis was conservative, and did not include the route-to-route (oral-to-inhalation) extrapolation factor, generally assumed to further reduce safe exposure levels. The purpose of MOE values, once below the FDA-defined safety margin of 10,000, is not to rank risk levels of individual compounds but to support regulatory agencies in the prioritization of chemicals for risk-mitigation.
Acknowledgements
Funding/Support: This work was supported by the National Institute of Environmental Health Sciences (NIEHS) (R01ES029435 to Dr. Sven-Eric Jordt).
Role of the Funder/Sponsor: The funding organization had no role in the preparation or interpretation of the data; review or approval of the manuscript; nor in the decision to submit the manuscript for publication. The content is solely the responsibility of the authors and does not necessarily represent the views of the funding agencies
Footnotes
Conflict of Interest Disclosures: Dr. Jabba reports no disclosures. Dr. Jordt reports personal fees and non-financial support from Hydra Biosciences and Sanofi, and non-financial support from GlaxoSmithKline Pharmaceuticals.
References
- 2.E-Cigarette-Forum. How much ejuice do you use?. [Forums]. 2017; https://www.e-cigarette-forum.com/threads/how-much-ejuice-do-you-use.831513/. Accessed 30th October, 2019.
- 3.Smets J, Baeyens F, Chaumont M, Adriaens K, Van Gucht D. When Less is More: Vaping Low-Nicotine vs. High-Nicotine E-Liquid is Compensated by Increased Wattage and Higher Liquid Consumption. Int J Environ Res Public Health. 2019;16(5). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Chaumont M, de Becker B, Zaher W, et al. Differential Effects of E-Cigarette on Microvascular Endothelial Function, Arterial Stiffness and Oxidative Stress: A Randomized Crossover Trial. Sci Rep. 2018;8(1):10378. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.European-Medicines-Agency . Public statement on the use of herbal medicinal products1 containing pulegone and menthofuran. In: Agency EM, ed. EMA/HMPC/138386/2005 Rev. 12016.
- 6.FDA. Food Additive Regulations; Synthetic Flavoring Agents and Adjuvants. In: FDA, ed. Vol 83 FR 50490 Federal Register2018: 50490–50503. [Google Scholar]