Abstract
The use of flavoring substances is an important element in the development of reduced-risk products for adult smokers to increase product acceptance and encourage switching from cigarettes. In a first step towards characterizing the sub-chronic inhalation toxicity of neat flavoring substances, a study was conducted using a mixture of the substances in a base solution of e-liquid, where the standard toxicological endpoints of the nebulized aerosols were supplemented with transcriptomics analysis. The flavor mixture was produced by grouping 178 flavors into 26 distinct chemical groups based on structural similarities and potential metabolic and biological effects. Flavoring substances predicted to show the highest toxicological effect from each group were selected as the flavor group representatives (FGR). Following Organization for Economic Cooperation and Development Testing Guideline 413, rats were exposed to three concentrations of the FGR mixture in an e-liquid composed of nicotine (23 µg/L), propylene glycol (1520 µg/L), and vegetable glycerin (1890 µg/L), while non-flavored and no-nicotine mixtures were included as references to identify potential additive or synergistic effects between nicotine and the flavoring substances. The results indicated that the inhalation of an e-liquid containing the mixture of FGRs caused very minimal local and systemic toxic effects. In particular, there were no remarkable clinical (in-life) observations in flavored e-liquid-exposed rats. The biological effects related to exposure to the mixture of neat FGRs were limited and mainly nicotine-mediated, including changes in hematological and blood chemistry parameters and organ weight. These results indicate no significant additive biological changes following inhalation exposure to the nebulized FGR mixture above the nicotine effects measured in this sub-chronic inhalation study. In a subsequent study, e-liquids with FGR mixtures will be aerosolized by thermal treatment and assessed for toxicity.
Highlights
For many decades, the foundational strategy for reducing smoking-related harm has been focused on preventing smoking initiation and promoting smoking cessation (Golechha 2016)
There is a large number of flavoring substances that can be potentially used in reducedrisk products1 (RRP), and most of them are generally recognized as safe (GRAS) for use in food products (Hallagan 2016; Smith et al 2003); there are limited data available on the safety of these flavoring substances in the context of inhalation (Helen et al 2017; Kaur et al 2018; Werley et al 2016)
Given the specific aim for which RRPs are conceived for potential harm reduction, flavoring substances should be subjected to appropriate quality and safety standards to ensure that they are safe in the context of their intended use
Summary
The foundational strategy for reducing smoking-related harm has been focused on preventing smoking initiation and promoting smoking cessation (Golechha 2016). The best way to reduce smoking-related harm is to quit tobacco use altogether. For adult smokers who would otherwise continue to smoke, switching to reducedrisk products (RRP) that emit significantly lower levels of harmful and potentially harmful constituents compared with those from cigarette smoke, may reduce the harm. It is important that adult smokers find these alternatives satisfying compared to smoking cigarettes. The use of flavoring substances is an important factor in the development of RRPs to maximize product acceptance by adult smokers and encourage them to switch away from cigarettes. There is a large number of flavoring substances that can be potentially used in RRPs, and most of them are generally recognized as safe (GRAS) for use in food products (Hallagan 2016; Smith et al 2003); there are limited data available on the safety of these flavoring substances in the context of inhalation (Helen et al 2017; Kaur et al 2018; Werley et al 2016).
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