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With the growing prevalence of e-cigarettes as an alternative to conventional cigarettes amongst smokers worldwide, there is a need for new methods to evaluate their relative toxicological profile as part of a safety assessment. Initiatives to replace, reduce and refine animal testing have led to developments of new methodologies utilizing organotypic, in vitro tissue models. Here we use a respiratory epithelial model, EpiAirway, to examine the biological effects of nicotine-containing blu PLUS + e-cigarettes, with or without blueberry flavoring, in comparison to conventional cigarette smoke. Tissues were exposed at the air-liquid interface to cigarette smoke or e-cigarette aerosol generated using a VITROCELL VC1 smoking/vaping robot. Following exposure to cigarette smoke, there was a significant decrease in tissue viability and barrier function. Additionally, secretion of inflammatory cytokines, interleukin 6 and 8 (IL-6, IL-8) altered and a marker of DNA damage, γ-H2AX, was significantly increased. Conversely, tissues exposed to up to 400 puffs of e-cigarette aerosol with or without blueberry flavor did not differ compared to air-exposed tissues in any of the measured endpoints. Overall, the tested e-cigarette products induced significantly less cytotoxicity than conventional cigarette smoke under the conditions of test and suggest such products have the potential for reduced health risks. Our results also demonstrate that organotypic tissue models are useful for assessing the biological impact of e-cigarettes and their flavorings., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Electronic cigarettes (e-cigarettes) are an increasingly popular alternative to combustible tobacco cigarettes among smokers worldwide. A growing body of research indicates that flavours play a critical role in attracting and retaining smokers into the e-cigarette category, directly contributing to declining smoking rates and tobacco harm reduction. The responsible selection and inclusion levels of flavourings in e-liquids must be guided by toxicological principles. Some flavour ingredients, whether natural extracts or synthetic, are known allergens. In this study, we used the Genomic Allergen Rapid Detection (GARD) testing strategy to predict and compare the respiratory and skin sensitising potential of three experimental and two commercial e-liquids. These novel, myeloid cell-based assays use changes in the transcriptional profiles of genomic biomarkers that are collectively relevant for respiratory and skin sensitisation. Our initial results indicate that the GARD assays were able to differentiate and broadly classify e-liquids based on their sensitisation potential, which are defined mixtures. Further studies need to be conducted to assess whether and how these assays could be used for the screening and toxicological assessment of e-liquids to support product development and commercialisation., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

The safety profile of Puritane™, a closed system electronic vapour product (EVP), was evaluated when used by smokers of conventional cigarettes (CCs) for 24 months in a real-life setting. The study was a two-centre ambulatory clinical study with 209 healthy volunteers. Outcome measures included adverse events (AEs), vital signs, electrocardiogram, lung function tests, exposure to nicotine and selected smoke constituents, nicotine withdrawal effects and smoking desire. No serious AEs related to EVP use were observed. The most frequently reported AEs were headache, nasopharyngitis, sore throat and cough, reported by 28.7%, 28.7%, 19.6% and 16.7% of subjects, respectively, which dissipated over time. Small decreases in lung function were not considered clinically relevant. No clinically relevant findings were observed in the other safety parameters. From Month 2, nicotine withdrawal symptoms decreased. Smoking desire and CC consumption steadily decreased over time in all subjects. EVP use was associated with reduced exposure to cigarette smoke constituents, whereas urinary nicotine levels remained close to baseline. Body weight did not increase in CC subjects switching to the EVP. In conclusion, the aerosol of the EVP at study was well tolerated and not associated with any clinically relevant health concerns after usage for up to 24 months., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

A randomised, parallel group clinical study was performed to evaluate the safety profile of an e-vapour product (EVP; 2.0% nicotine) in smokers of conventional cigarettes (CCs) switching to use the EVP for 12 weeks. During the study, no clinically significant product-related findings were observed in terms of vital signs, electrocardiogram, lung function tests and standard clinical laboratory parameters. Adverse events (AEs) reported by EVP subjects were more frequent during the first week after switching to the EVP. The frequency of AEs reduced thereafter and out of a total of 1515 reported AEs, 495 were judged as being related to nicotine withdrawal symptoms. The most frequently stated AEs were headache, sore throat, desire to smoke and cough reported by 47.4, 27.8, 27.5 and 17.0% of subjects, respectively. Only 6% of AEs were judged as probably or definitely related to the EVP. Additional observations in EVP subjects included a decrease in the level of urine nicotine equivalents by up to 33.8%, and decreases in the level of three biomarkers of exposure to toxicants known to be present in CC smoke (benzene, acrolein and 4-[methylnitrosamino]-1-[3-pyridyl]-1-butanone). The decrease in nicotine equivalents coincided with an increase in nicotine withdrawal symptoms, measured by a questionnaire, which subsided after two weeks. The data presented here shows the potential EVPs may offer smokers looking for an alternative to CCs., (Crown Copyright © 2016. Published by Elsevier Inc. All rights reserved.)

An Electronic Vapour Product (EVP) has been evaluated for short-term safety parameters and subjective effects in a 2-part study, in smokers. Part 1 compared the EVP with unflavoured (UF) and flavoured (FL) e-liquid at 2.0% nicotine to a conventional cigarette (CC; JPS Silver King Size, 0.6 mg) and a licensed nicotine inhalator (Nicorette(®), 15 mg). Part 2 assessed the effect of increasing concentrations of nicotine in the e-liquid used with the EVP (0%, 0.4%, 0.9%, 2.0%). The study was designed as a randomised, controlled, crossover trial. Outcomes included adverse events (AEs), vital signs, exhaled carbon monoxide (CO), clinical laboratory parameters, smoking urges and withdrawal symptoms. In both study parts, only mild non-serious AEs were reported. No major differences were observed in AEs between the EVPs and Nicorette(®). Exhaled CO levels only increased for CC. All products appeared to decrease smoking urges and nicotine withdrawal symptom scores to a similar extent. The EVP had a similar short-term safety profile to Nicorette(®) and relieved smoking urges and nicotine withdrawal symptoms to a similar extent as Nicorette(®) and CC. Unlike nicotine replacement therapies, the EVP may offer an alternative for those finding it difficult to quit the behavioural and sensorial aspects of smoking., (Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.)

The pharmacokinetic (PK) profile of nicotine delivered by an Electronic Vapour Product (EVP) was characterised in a 2-part study in smokers. The study was designed as a randomised, controlled, four-way crossover trial. Part 1 compared an unflavoured e-liquid (UF2.0%) and a flavoured e-liquid (FL2.0%) to a conventional cigarette (CC; JPS Silver King Size, 0.6 mg) and a licensed nicotine inhalator (Nicorette(®); 15 mg). Part 2 compared e-liquids with increasing nicotine concentrations (0%, 0.4%, 0.9%, 2.0%). Subjects used each different product for a daily use session. In Part 1, maximum plasma nicotine concentration (Cmax) for UF2.0%, FL2.0%, Nicorette(®) and CC was 3.6, 2.5, 2.5 and 21.2 ng/mL, respectively. The time to maximum plasma nicotine concentration (Tmax) was longer for the EVP (UF2.0%, 9.0 min; FL2.0%, 10.0 min) and the nicotine inhalator (13.0 min) compared to CC (3.0 min). In Part 2, EVP with 0%, 0.4%, 0.9% and 2.0% nicotine produced Cmax values of 0.6, 1.0, 1.9 and 3.6 ng/mL, respectively. At the maximum nicotine concentration of 2% as prescribed by the European Tobacco Directive, the EVP achieved nicotine delivery that was comparable to the inhalator. EVPs thus offer a potential alternative to nicotine inhalator devices for those finding it difficult to quit smoking., (Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.)