We are pleased to provide again these updates from some of the student-authors whose research appeared in this and in past special volumes of Frontiers. These updates serve as a testimony to the ongoing impact of the study abroad experience, and inspire everyone involved with study abroad to value the distinctiveness of study abroad learning.
. Variability in biomarker of exposure levels in smokers in a study of smokers switched to reduced toxicant prototype cigarettes. Christopher J. Shepperd1, Alison Eldridge1, Graham Errington1, Oscar M Camacho1, Kevin McAdam1, Ingo Meyer2 and Christopher J. Proctor1* 1British American Tobacco, Group Research & Development, Regents Park Road, Southampton, SO15 8TL, United Kingdom 2Momentum Pharma Services, Hamburg, Germany *Correspondence: christopher_proctor@bat.com
During cigarette smoking, nicotine deposition in the mouth, upper airways and deep lung can occur via rapid diffusion of gas-phase nicotine and via deposition of particle-bound nicotine, with changing proportions, dependent on physical and chemical equilibria. We have used a diffusion denuder approach to physical equilibria to evaluate comprehensively the percentage of nicotine that is initially in the gas phase of mainstream cigarette smoke under different temperature (T) and relative humidity (RH) conditions. Smoking experiments with University of Kentucky 3R4F research cigarettes were performed at six denuder T values (291–335 K) and three RH values (30%, 45% and 60%). G/P partitioning of nicotine increased significantly with increasing T, and decreased substantially with increasing RH. The measured gas diffusion coefficient of nicotine in the system, D298K = 0.071 ± 0.006 cm2 s−1, was consistent with published data. Application of the theoretical denuder model of Lipowicz and Piadè indicated that the initial gas-phase fraction (fgLP) of nicotine entering the denuder tube ranged from ≈ 0.012% to 7.2% depending on T and RH. The fgLP values were used to derive the G/P partitioning constant, Kp, proposed by Pankow, ranging from 1.61e-06 to 1.06e-03. The first reported use of van't Hoff plots of Kp yielded an enthalpy change of 110 kJ mol−1, consistent with the thermodynamics of the solution process and the acid–base equilibrium of nicotine in droplets of mainstream smoke. These new data offer scope for improved modelling of nicotine behaviour in tobacco smoke and its subsequent deposition in the respiratory tract.
The concept of a risk continuum for tobacco and nicotine products has been proposed, which differentiates products according to their propensity to reduce toxicant exposure and risk. Cigarettes are deemed the most risky and medicinal nicotine the least. We assessed whether a Reduced-Toxicant Prototype (RTP) cigarette could sufficiently reduce exposure to toxicants versus conventional cigarettes to be considered a distinct category in the risk continuum. We present findings from both pre-clinical and clinical studies in order to examine the potential for reduced smoke toxicant emissions to lower health risks associated with cigarette smoking. We conclude that current toxicant reducing technologies are unable to reduce toxicant emissions sufficiently to manifest beneficial disease-relevant changes in smokers. These findings point to a minimum toxicant exposure standard that future potentially reduced risk products would need to meet to be considered for full biological assessment. The RTP met WHO TobReg proposed limits on cigarette toxicant emissions, however the absence of beneficial disease relevant changes in smokers after six months reduced toxicant cigarette use, does not provide evidence that these regulatory proposals will positively impact risks of smoking related diseases. Greater toxicant reductions, such as those that can be achieved in next generation products e.g. tobacco heating products and electronic cigarettes are likely to be necessary to clearly reduce risks compared with conventional cigarettes.
Vapour products have demonstrated potential to be a lower-risk alternative to cigarettes. The present study describes a novel hybrid tobacco product that combines a warm aerosol stream generated by an electronic vaporisation mechanism with tobacco top flavour from cut tobacco. During operation, the aerosol stream released from the vapour cartomiser is passed through a bed of blended cut tobacco by the puffing flow, elevating the tobacco temperature and eluting volatile tobacco flavour components. A preliminary but comprehensive analysis of the aerosol composition of the hybrid tobacco product found that emissions were dominated by the control vapour formulation. In non-targeted chemical screening, no detectable difference in GC scans was observed between the hybrid tobacco product and the control vapour product. However, a sensorially elevated tobacco flavour was confirmed by a consumer sensory panel (P < 0.05). In a targeted analysis of 113 compounds, either identified by regulatory bodies as potential toxicants in cigarette smoke or formed from electronic vapour products, only 26 were quantified. The novel action of tobacco heating and liquid aerosolisation produced classes and levels of toxicants that were similar to those of the control vapour product, but much lower than those of a Kentucky 3R4F reference cigarette. For nine toxicants mandated by the WHO Study Group on Tobacco Product Regulation for reduction in cigarette emissions, the levels were 91%–99% lower per puff in the hybrid tobacco product aerosol than in 3R4F smoke. Overall, the novel hybrid tobacco product provides a sensorially enhanced tobacco flavour, but maintains a toxicant profile similar to its parent vapour product with relatively low levels of known cigarette smoke toxicants.
There has been increased interest in recent years in regulatory reporting of cigarette smoke toxicants. There is a great deal of diversity in current regulatory standards around the world in terms of the identities of regulated toxicants, and the number of replicate analyses stipulated for their measurement. Furthermore, analytical methods developed collaboratively by several organisations and intended for regulatory analysis generally differ in their recommended replicate numbers to those stipulated by regulators. In view of these inconsistencies, we undertook an exercise to examine the most appropriate numbers of replicates required for regulatory analysis of cigarette smoke toxicants. A one-point-in-time sampling exercise was undertaken of the German cigarette market, with 161 brands sampled and analysed in a single laboratory using Canadian Intense smoking conditions. Seven replicate measurements were made for each analyte and product, other than nicotine, CO and nicotine-free dry particulate matter for which eight replicate measurements were made. After confirming the absence of order of analysis effects, a variety of statistical tests (such as group assessment, paired comparisons, linear regression models and ratio analysis) were conducted examining mean values, SDs and CVs to identify the role of numbers of analytical replicates on data quality. The statistical analysis showed no difference in mean values for any of the 18 toxicants irrespective of replicate numbers (between 3 and 7 or 8). The large majority of analytes showed no difference in data variability with replicate number; but some very small differences (much lower than within product variability) were observed for a minority of compounds. Similarly, paired analysis showed no significant differences between mean values obtained using different replicate numbers in most cases, apart from very low differences (<5%) for a small number. Linear regression analysis showed correlations around 96 to 98% (other than crotonaldehyde at 91%) between values obtained with 3 vs 7 replicates. Similarly, per product mean value ratio analysis showed 95% consistency between values obtained with 3 and 7 replicates. We therefore conclude that three replicates is sufficient for precise determination of cigarette mainstream smoke toxicant emissions, and that use of 7 replicates as stipulated in some regulator jurisdictions does not offer any greater accuracy or precision.
Snus is a smokeless oral tobacco product with a significant history of use in Sweden, where it is regulated under food legislation. Users place a small porous sachet or a pinch of loose snus between the upper jaw and cheek for approximately one hour, leading to partial intake of tobacco constituents. To understand user exposure to tobacco, a multi-analyte approach based on the extraction of pouches by methanol, ethanol and water was validated and applied to the measurement of various constituents, including nicotine, four tobacco-specific nitrosamines (TSNAs), propylene glycol, water, ammonium, nitrate, sodium, chloride, linalool, citronellol, linalyl acetate and geraniol, extracted from snus pouches during use by human consumers.After validation against established single-analyte methods, the multi-analyte approach was used to determine constituent levels in snus pouches before and after one hour of use. Although the concentrations in the snus pouches varied from nanogram (e.g. TSNAs) to milligram (e.g. nicotine, sodium and propylene glycol) quantities (25.1 ng to 35.3 mg per 1 g pouch), the mean percentage extracted varied only from 19.2% for linalyl acetate to 37.8% for the TSNA 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) among all constituents analyzed. The TSNAs, some of which are known carcinogens, showed the highest percentage extraction (range 34.6%-37.8%). Measurement variability was low for all analytes, ranging from 2.4% (total TSNAs, NAT) to 9.5% (geraniol). By contrast, inter-subject variability ranged from 6.7% (NAB) to 52.2% (linalyl acetate), and was greater than 20% for eight of the constituents analyzed. Intra-subject variability ranged from 3.4% (citronellol) to 29.7% (geraniol).Generally, less than a third of each constituent tested was extracted during one hour of snus use, independent of constituent concentration. The variable nature of in-use extraction was shown to be driven by inter-subject variability. The results provide insight into possible mechanisms controlling constituent extraction in the mouth during snus use, and provide reference data for the development of in-vitro laboratory systems for estimating extraction of tobacco constituents from snus.
This series of nine papers described the operation and pre-clinical assessment of a tobacco heating product THP1.0. This last paper contextualises the pre-clinical assessment data on THP1.0 with data from other next generation products relative to cigarette smoke. The tobacco and nicotine risk continuum is a concept that ranks products according to their potential harm, with cigarettes at the highest risk extreme and Nicotine Replacement Therapy at the least risky extreme. Data generated in pre-clinical studies on THP1.0 and a range of Next Generation Products (NGPs) may provide some initial indication of potential ranking of these products, although importantly, data from such studies are limited and cannot take into consideration several important aspects for risk such as long term product use patterns. In each of the studies, the responses to the emissions from THP1.0 were substantially reduced relative to cigarette smoke. Additionally, responses from THP1.0 were very similar to those from the other NGP emissions. A comparison of the results clearly showed the emissions from all the NGPs were considerably lower than those from cigarettes and all in around the same emissions level. These results show that THP1.0 could have the potential to be a reduced risk product compared to cigarettes, though further studies assessing the exposure, individual and population risk reduction profile would be required to substantiate this potential.
The Institute of Medicine encouraged the pursuit and development of potential reduced-exposure products, tobacco products that substantially reduce exposure to one or more tobacco toxicants and can reasonably be expected to reduce the risk of one or more specific diseases or other adverse health effects. One approach to reducing smoke toxicant yields is to dilute the smoke with glycerol. We report chemical, biological and human exposure data related to experimental cigarettes containing up to 60% of a novel glycerol containing "tobacco-substitute" sheet. Analysis of mainstream smoke from experimental cigarettes showed reductions in yields of most measured constituents, other than some volatile species. In vitro toxicological tests showed reductions in the activity of smoke particulates in proportion to their glycerol content. Human exposure to nicotine was reduced by a mean of 18% as determined by filter studies and by 14% using 24h urinary biomarker analysis. Smoke particulate exposures were reduced by a mean of 29% in filter studies and NNK exposure by similar amounts based on urinary 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol concentrations. These results show that reducing exposure to some smoke toxicants is possible using a tobacco-substitute sheet, although some smoke toxicants, and the sensory attributes of the smoke, remain as technical challenges.
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