Changes in Biomarkers of Exposure on Switching From a Conventional Cigarette to Tobacco Heating Products: A Randomized, Controlled Study in Healthy Japanese Subjects.

BACKGROUND: Smoking is a leading cause of numerous human disorders including pulmonary disease, cardiovascular disease, and cancer. Disease development is primarily caused by exposure to cigarette smoke constituents, many of which are known toxicants. Switching smokers to modified risk tobacco products (MRTPs) has been suggested as a potential means to reduce the risks of tobacco use, by reducing such exposure. METHODS: This randomized, controlled study investigated whether biomarkers of toxicant exposure (BoE) were reduced when smokers switched from smoking combustible cigarettes to using a novel (glo™/THP1.0) or in-market comparator (iQOS/THS) tobacco heating product (THP). One hundred eighty Japanese smokers smoked combustible cigarettes during a 2-day baseline period, followed by randomization to either continue smoking cigarettes, switch to using mentholated or non-mentholated variants of glo™, switch to using a non-mentholated variant of iQOS, or quit nicotine and tobacco product use completely for 5 days. Baseline and post-randomization 24-h urine samples were collected for BoE analysis. Carbon monoxide was measured daily in exhaled breath (eCO). RESULTS: On day 5 after switching, urinary BoE (excluding for nicotine) and eCO levels were significantly (p < .05) reduced by medians between 20.9% and 92.1% compared with baseline in all groups either using glo™ or iQOS or quitting tobacco use. Between-group comparisons revealed that the reductions in the glo™ groups were similar (p > .05) to quitting in many cases. CONCLUSIONS: glo™ or iQOS use for 5 days reduced exposure to smoke toxicants in a manner comparable to quitting tobacco use. THPs are reduced exposure tobacco products with the potential to be MRTPs. IMPLICATIONS: This clinical study demonstrates that when smokers switched from smoking combustible cigarettes to using tobacco heating products their exposure to smoke toxicants was significantly decreased. In many cases, this was to the same extent as that seen when they quit smoking completely. This may indicate that these products have the potential to be reduced exposure and/or reduced risk tobacco products when used by smokers whose cigarette consumption is displaced completely. CLINICAL TRIAL REGISTRATIONS: ISRCTN14301360 and UMIN000024988.

Nicotine pharmacokinetics of electronic cigarettes: A review of the literature.

E-cigarettes are battery-powered electronic devices from which users can inhale nicotine following its aerosolisation from a liquid solution. Some regulators and public health bodies consider e-cigarettes as potentially playing a major role in tobacco harm reduction. Their ability to provide nicotine to smokers in both amount and in a manner and form generally similar to cigarette smoking have been proposed as key components to help smokers reduce or cease the use of combustible cigarettes. Nicotine pharmacokinetic studies of e-cigarettes have been performed for a number of years and are beginning to show how nicotine delivery is evolving as the products themselves evolve. In this review, we provide a critical overview of the literature to describe what is known about nicotine delivery from e-cigarettes. We will discuss how the progression of e-cigarette design, development, and user familiarity has allowed increases in nicotine availability to the user, in the context of how much and how rapidly nicotine is delivered during acute-use periods. This review will also provide insight into current research gaps and highlight the potential utility of modelling and the standardisation of methodologies used to assess nicotine delivery to facilitate identification of products that are best suited to displace cigarette smoking among adult smokers.

A randomised, controlled, two-Centre open-label study in healthy Japanese subjects to evaluate the effect on biomarkers of exposure of switching from a conventional cigarette to a tobacco heating product.

BACKGROUND: Smoking is a leading cause of numerous human disorders including lung cancer, chronic obstructive pulmonary disease, and atherosclerotic cardiovascular disease. The development of modified risk tobacco products (MRTPs) has been suggested as a possible way to reduce the risks of tobacco smoking by reducing exposure to cigarette smoke toxicants. This study is designed to investigate whether biomarkers of such exposure are reduced when smokers switch from smoking commercial cigarettes to using either a novel or a commercially-available tobacco heating product (THP). DESIGN AND METHODS: This study will assess biomarkers of exposure in current smokers who either remain smoking, switch to THP use, or quit all tobacco use completely, for 5 days. The study is an in-clinic (confinement) two-centre, randomised controlled clinical study with a forced-switching design. Subjects of either gender will be aged 23-55 years (minimum legal smoking age plus 3 years), of Japanese origin and with a verified smoking status (assessed by exhaled breath carbon monoxide and urinary cotinine levels). Subjects will have a usual brand cigarette within the International Organisation for Standardisation (ISO) tar band of 6-8 mg and will be judged to be healthy by medical history, physical examination, vital signs, electrocardiography (ECG), clinical biochemistry and lung function tests. The primary objective of this study is to assess changes within groups in selected biomarkers of exposure (BoE) and of biological effect (BoBE) after a forced switch from a commercial control cigarette to either a menthol or a non-menthol THP. Secondary objectives are to assess between-group differences, to determine nicotine pharmacokinetics for cigarettes and THPs, to assess subject's satisfaction with the study products, and to monitor additional endpoints related to safety and product use. DISCUSSION: Data from this study will advance our scientific understanding of the changes in exposure to cigarette smoke toxicants in smokers who switch to using a THP. TRIAL REGISTRATIONS: UMIN000024988 (25th November 2016); ISRCTN14301360 (14th December 2016).

Impact assessment of WHO TobReg proposals for mandated lowering of selected mainstream cigarette smoke toxicants.

The WHO Tobacco Product Regulation Study Group (TobReg) has proposed three regulatory models for cigarettes, each creating mandatory limits for emissions of nine smoke toxicants. One approach proposes country-specific limits, using median or 1.25× median toxicant/nicotine emission ratios. A second model provides fixed toxicant-ratio limits. The third model limits were three times the lowest toxicant emission on a market. Currently, the practical implications of these models are largely unknown. An impact assessment was conducted using cigarette data from 79 countries to identify four diverse test markets. We sampled all products from each market but limited product availability led to incomplete (80-97%) sourcing. Analysis showed that the country-specific model led to diverse (up to threefold) toxicant limits across the four markets. 70%-80% of products were non-compliant, rising to 100% in some countries with the second and the third models. With each regulatory model the main drivers of non-compliance were the tobacco-specific nitrosamines, the simultaneous application of limits for nine poorly correlated smoke toxicants, and analytical variability. Use of nicotine ratios led to compliance of some high toxicant emission products due to high nicotine emissions. Our findings suggest that these proposals would have greater impact on global markets than TobReg's stated aims.

A study to evaluate the effect on Mouth Level Exposure and biomarkers of exposure estimates of cigarette smoke exposure following a forced switch to a lower ISO tar yield cigarette.

A forced switch to a lower ISO tar yield cigarette was used in a clinical study, conducted in Germany, that compared two methods of estimating exposure to cigarette smoke. Pre- and post-switch estimates of Mouth Level Exposure (MLE) to nicotine, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), pyrene and acrolein were obtained by chemical analysis of spent cigarette filters for nicotine content. Similarly, pre- and post-switch estimates of uptake of these smoke constituents were achieved by analysis of corresponding urinary biomarkers of exposure (BoE): total nicotine equivalents; total 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL); total 1-hydroxypyrene (1-OHP), and 3-hydroxypropyl-mercapturic acid (3-HPMA), plus the nicotine metabolite cotinine, in plasma and saliva. Three hundred healthy volunteers were recruited comprising 100 smokers of each of 9-10 and 4-6 mg ISO tar yield cigarettes and 50 smokers of 1-2mg ISO tar yield cigarettes and 50 non-smokers. Fifty smokers of each of the 9-10 and 4-6 mg ISO tar yield cigarettes took part in the switching aspects of this study whilst the remaining smokers formed non-switching control groups who smoked their usual ISO tar yield cigarette throughout the study. After 5 days, all subjects were admitted into a clinic where baseline measures of MLE and BoE were obtained. The 10mg switching group was then switched to the 4 mg ISO tar yield cigarette and the 4 mg ISO tar yield switching group switched to the 1mg cigarette. Subjects returned home for 12 days, continuing to smoke the supplied cigarettes before being readmitted into the clinic where samples were collected for MLE and BoE analysis. Changes in daily exposure estimates were determined on a group and individual basis for both methods. The pre- to post-switch directional changes in MLEs and their corresponding BoEs were generally consistent and the MLE/BoE relationship maintained. Switching to a lower yield cigarette generally resulted in reductions in exposure with the resultant exposure level being similar to that seen in regular smokers of the lower yield cigarette.

Estimation and correlation of cigarette smoke exposure in Canadian smokers as determined by filter analysis and biomarkers of exposure.

A clinical study conducted in Canada compared two methods of estimating exposure to cigarette smoke in 192 volunteer subjects: 43 smokers of 4-6 mg, 49 of 8-12 mg and 50 of 14-15 mg ISO tar yield cigarettes and 50 non-smokers. Estimates of mouth level exposure (MLE) to nicotine, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), pyrene and acrolein were obtained by chemical analysis of spent cigarette filters. Estimates of smoke constituent uptake were achieved by analysis of urinary biomarkers for total nicotine equivalents (nicotine, cotinine, trans-3'-hydroxycotinine plus their glucuronide conjugates), NNK (total 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) plus glucuronide), pyrene (1-hydroxy pyrene plus glucuronide) and acrolein (3-hydroxylpropyl-mercapturic acid) plus the nicotine metabolite cotinine in plasma and saliva. The objective of our study was to confirm the correlations between measures of human exposure obtained by filter analysis and biomarkers. Significant correlations (p<0.001) were found between MLE and the relevant biomarker for each smoke constituent. The adjusted values of the Pearson correlation coefficients (r) were 0.80 (nicotine), 0.77 (acrolein) and 0.44 (pyrene). NNK correlations could not be obtained because of the low NNK yield of Canadian cigarettes. Unexpectedly high levels of acrolein biomarker found in non-smokers urine on one of the two days sampled emphasised the need for more than one sampling occasion per period and an awareness of non-tobacco sources of smoke constituents under investigation. No consistent dose response, in line with ISO tar yield smoked, of MLE estimates was found for nicotine, pyrene and acrolein and respective biomarkers. The influence of demographics on our results has also been examined.

A study to estimate and correlate cigarette smoke exposure in smokers in Germany as determined by filter analysis and biomarkers of exposure.

A clinical study, conducted in Germany, compared two methods of estimating exposure to cigarette smoke. Estimates of mouth level exposure (MLE) to nicotine, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), pyrene and acrolein were obtained by chemical analysis of spent cigarette filters for nicotine content. Estimates of smoke constituent uptake were achieved by analysis of corresponding urinary biomarkers: for nicotine; total nicotine equivalents (nicotine, cotinine, trans-3'-hydroxycotinine plus their glucuronide conjugates), for NNK; (4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) plus glucuronide, for pyrene; 1-hydroxy pyrene (1-OHP) plus glucuronide and for acrolein; 3-hydroxylpropyl-mercapturic acid (3-HPMA) plus the nicotine metabolite cotinine in plasma and saliva. Two hundred healthy volunteer subjects were recruited; 50 smokers of each of 1-2 mg, 4-6 mg and 9-10 mg ISO tar yield cigarettes and 50 non-smokers (NS). Smokers underwent two periods of home smoking, each followed by residence in a clinic. Smoking was permitted ad libitum, and spent cigarette filters, cigarette consumption data, 24h urine, as well as plasma and saliva samples were collected. Significant correlations (p<0.001) were found between MLE and the relevant biomarker for each smoke constituent. The Pearson correlation coefficients (r) were 0.83 (nicotine), 0.76 (NNK), 0.82 (acrolein) and 0.63 (pyrene). Mean MLE estimates for nicotine, NNK and pyrene showed a dose response in line with ISO tar yield smoked, with 10 mg > 4 mg >1 mg, and for acrolein 10 mg> 4 mg > *1mg (where * indicates not significant at 95% confidence level). The mean exposure estimates from biomarkers for nicotine, NNK and acrolein also showed a dose response in line with ISO tar yield with 10 mg > 4 mg > 1 mg > NS, and for pyrene 10 mg > *4 mg> 1 mg> NS. This study shows that estimates of exposure obtained by filter analysis and biomarkers of exposure correlate significantly over a wide range of smoke exposures and that filter analysis may provide a simple and effective alternative to biomarkers for estimating smokers' exposure.