Influence of cigarette filter ventilation on smokers' mouth level exposure to tar and nicotine.

Cigarette filter ventilation allows air to be drawn into the filter, diluting the cigarette smoke. Although machine smoking reveals that toxicant yields are reduced, it does not predict human yields. The objective of this study was to investigate the relationship between cigarette filter ventilation and mouth level exposure (MLE) to tar and nicotine in cigarette smokers. We collated and reviewed data from 11 studies across 9 countries, in studies performed between 2005 and 2013 which contained data on MLE from 156 products with filter ventilation between 0% and 87%. MLE among 7534 participants to tar and nicotine was estimated using the part-filter analysis method from spent filter tips. For each of the countries, MLE to tar and nicotine tended to decrease as filter ventilation increased. Across countries, per-cigarette MLE to tar and nicotine decreased as filter ventilation increased from 0% to 87%. Daily MLE to tar and nicotine also decreased across the range of increasing filter ventilation. These data suggest that on average smokers of highly ventilated cigarettes are exposed to lower amounts of nicotine and tar per cigarette and per day than smokers of cigarettes with lower levels of ventilation.

E-cigarette Nicotine Delivery: Data and Learnings from Pharmacokinetic Studies.

OBJECTIVES: E-cigarettes could potentially play a major role in tobacco harm reduction by delivering nicotine in a vapor containing significantly fewer toxicants than cigarette smoke and may aid smoking behavior changes such as reduction or cessation. METHODS: We examined blood nicotine levels in smokers who were non-accustomed to e-cigarette use (Study 1) and accustomed e-cigarette users (Study 2). We compared nicotine levels when participants used a closed modular system e-cigarette to those when participants smoked a cigarette. RESULTS: In Study 1, Cmax (geometric mean (CV)) during a 5-minute puffing period (10 puffs, 30 seconds apart) was 13.4 (51.4) ng/ ml for a regular cigarette. The e-cigarette Cmax was significantly lower (p .05) at 2.5 (67.8) ng/ml. In Study 2, during a 5-minute ad libitum puffing period, cigarette Cmax was 7.2 (130.8) ng/mL, and it was 7.8 (108.2) ng/mL for the e-cigarette. CONCLUSIONS: Our data demonstrate heterogeneity of nicotine deliveries both between products and also with the same products used by different cohorts, eg, accustomed users versus smokers. Such differences must be taken into account when determining the likely behavioral impact, on smoking reduction and cessation, of nicotine delivery data and when planning e-cigarette nicotine pharmacokinetic studies.

Changes in levels of biomarkers of exposure and biological effect in a controlled study of smokers switched from conventional cigarettes to reduced-toxicant-prototype cigarettes.

BACKGROUND: Development of cigarettes that reduce exposure to harmful smoke constituents is a suggested tobacco harm reduction strategy, but robust methods for measurement of change are required. We investigated whether changes in biomarkers of exposure (BoE), effective dose (BoED) and biological effect (BoBE) could be detected after switching from conventional cigarettes to a reduced-toxicant-prototype cigarette (RTP). METHODS: Regular smokers of 6-8mg ISO tar yield cigarettes were recruited in Hamburg, Germany, and supplied with a conventional 7mg ISO tar yield cigarette for 2weeks then switched to the same cigarette with a different tipping paper (control) or the RTP for 6months. Subjects smoked mostly at home and attended five residential clinic visits where urine and blood samples were collected for analysis. Primary endpoints were changes in specific biomarker levels compared with non-smoker background levels. Changes in daily cigarette consumption were also investigated. RESULTS: BoE levels in controls generally increased over the study period, whereas most BoE and all BoED significantly declined in RTP smokers. Most BoBE data were similar across groups and/or too variable within individuals to detect changes. Increased daily cigarette consumption was affected by supply of free cigarettes, perceived shorter smoking time per cigarette than usual brands, and perceived reduced harm. CONCLUSIONS: Despite increased cigarette consumption, reductions in BoE and BoED were detectable.

Preliminary Evaluation of a New German Translated Tobacco Quality of Life Impact Tool to Discriminate Between Healthy Current and Former Smokers and to Explore the Effect of Switching Smokers to a Reduced Toxicant Prototype Cigarette.

BACKGROUND: Assessment of health-related quality of life (HRQoL) is well established in clinical research, but ceiling effects in validated tools might prevent detection of changes in well respondents. Tobacco Quality of Life Impact Tool (TQOLITv1) uses conceptual and psychometric advances to enhance detection of HRQoL changes. METHODS: In a 6-month, forced-switch study, the German TQOLITv1 was assessed in healthy adult (age 23-55 years) current and matched former-smokers. At baseline, smokers were switched to reduced toxicant prototype (RTP) or conventional cigarette for 6 months. TQOLITv1 responses were collected at baseline, 3 and 6 months from current smokers whilst former smokers completed it at the latter two time points. TQOLITv1 includes SF-36v2 and new smoking-specific, physical and general-health measures. RESULTS: Reliability at baseline was good (Cronbach's coefficient alpha > 0.70) for all measures. The baseline percentage with the best possible score (ceiling effect) for former and current smokers was substantially better for the new physical function than SF-36 physical function measure (35% vs. 59% at ceiling, respectively). New smoking-specific measures discriminated current from former smokers better than general health measures. Smoking-specific symptoms (r = 0.73) were more stable from baseline to 6 months than other measures (r = 0.38-0.54) particularly more than the SF-36 mental component score (r = 0.24). Although both product smoking groups worsened in most HRQoL measures, changes in general and smoking-specific HRQoL impact measures favored RTP smokers. CONCLUSIONS: The German TQOLITv1 is sufficiently reliable and valid to assess HRQoL and may be more useful than SF-36v2 in evaluation of interventions in well smoking populations including those consuming RTPs.

A cross-sectional analysis of candidate biomarkers of biological effect in smokers, never-smokers and ex-smokers.

CONTEXT: Biomarkers of biological effect (BOBE) have been proposed as potential tools to assess tobacco product use, toxicity and disease risk. OBJECTIVE: To determine if candidate BOBE can distinguish between smokers, never-smokers and former smokers. METHODS: Biomarker levels were compared from 143 smokers, 61 never-smokers and 61 ex-smokers. RESULTS: In total, 27 candidate biomarkers were assessed, 14 were significantly different between smokers and never-smokers (p < 0.01) and of these 14 biomarkers, 12 were able to distinguish between smokers and former smokers (p < 0.05), which indicates the potential for reversibility. CONCLUSIONS: A total of 12 of 27 BOBE are potentially useful tools for future product assessment.

Reference change values to assess changes in concentrations of biomarkers of exposure in individuals participating in a cigarette-switching study.

BACKGROUND: In a previous clinical study, levels of biomarkers of exposure (BoEs) for specific toxicants were significantly reduced in smokers who switched from conventional cigarettes to reduced toxicant prototype (RTP) cigarettes. Very little is known about the biological variability of tobacco smoke BoEs within individuals and sub-groups, and the descriptive group-comparison statistics might not be sufficient to understand such changes. Therefore, we assessed how different statistical methods could be used to interpret changes in urine BoE levels at the individual level. METHODS: We used non-parametric statistical reference limits, the empirical rule and reference change values (RCVs) to assess changes in levels of BoEs related to four toxicants in cigarettes smoke. Current smokers [of 6 mg and 1 mg International Organization for Standardization (ISO) tar yields] were allocated to switching to RTP groups or non-switching control groups within their respective tar bands. There were two 6 mg tar study groups, with a non-switching group (CC6, n=46) and a group switching to an RTP containing tobacco-substitute sheet and modified filter (TSS6, n=49); and three 1 mg tar smoker groups, with one non-switching (CC1, n=42), a group switching to an RTP containing tobacco-substitute sheet and modified filter (TSS1, n=44) and one switching to an RTP containing an enzyme-treated tobacco and modified filter (BT1, n=47). RESULTS: Assessment of the direction of change showed that up to the 100% of subjects experienced a decrease in levels of some BoEs. Between 49% and 64% of subjects in the switching groups were classified as having decreased levels of 3-hydroxy-1-methylpropylmercapturic acid (HMPMA) by the non-parametric criterion, whereas only 2%-6% had reduced levels of N-nitrosoanatabine (NAT). Of non-switchers, in 7%-14% of those smoking 1 mg ISO tar yield cigarettes increases were classified across all BoEs. RCVs highlighted patterns with more detail, showing that most changes occurred within 14 days of switching. Among smokers who switched to 6 mg RTPs, 40%, 44%, 6% and 15%, respectively, were classified as experiencing significant decreasing levels of HPMA, 3-hydroxypropylmercapturic acid, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol and NAT, whereas in the two 1 mg switching groups 46%, 22%, 11% and 52% and 43%, 27%, 2% and 16% had decreased levels of the same biomarkers. Up to five subjects in the 6 mg non-switching group were classified as having increased levels of all BoEs. CONCLUSIONS: Although we believe that is not possible to determine whether the observed changes in BoEs reflect biological relevance, the use of reference values enables assessment of changes in BoEs at the individual level. Estimates of the BoE variability between subjects might aid study design and setting minimum targets for smoke toxicant yields for future development of RTPs.

A single-blinded, single-centre, controlled study in healthy adult smokers to identify the effects of a reduced toxicant prototype cigarette on biomarkers of exposure and of biological effect versus commercial cigarettes.

BACKGROUND: Despite universal acceptance that smoking is harmful, a substantial number of adults continue to smoke. The development of potential reduced exposure products (more recently termed modified risk tobacco products) has been suggested as a way to reduce the risks of tobacco smoking. This trial is designed to investigate whether changes in toxicant exposure after switching from a commercial to reduced toxicant prototype (RTP) cigarette (7 mg International Organisation for Standardisation (ISO) tar yield) can be assessed by measurement of biomarkers and other factors. The primary objective is to descriptively assess changes in selected biomarkers of exposure (BoE) and biomarkers of biological effect (BoBE) within participants and within and between groups after switching. Secondary objectives are to assess similarly changes in other biomarkers, quality of life, smoking behaviours, physiological measures, mouth-level exposure to toxicants and sensory perception. METHODS/DESIGN: This trial will assess current smokers, ex-smokers and never-smokers in a single-centre single-blind, controlled clinical trial with a forced-switching design and in-clinic (residential) and ambulatory (non-residential) periods. Smokers will be aged 23-55 years (minimum legal smoking age plus 5 years) and non-smokers 28-55 years (minimum legal smoking age plus 5 years, plus minimum 5 years since last smoked). Smokers will be allowed to smoke freely at all times. We will assess changes in selected BoE and BoBE and effective dose in urine and blood after switching. Creatinine concentrations in serum, creatinine clearance in urine, cotinine concentration in saliva, diaries and collection of spent cigarette filters will be used to assess compliance with the study protocol. Mouth-level exposure to toxins will be assessed by filter analysis. DISCUSSION: Data from this study are expected to improve scientific understanding of the effects of RTP cigarettes on BoE and BoBE, and give insights into study design for clinical assessment of potential MRTPs. TRIAL REGISTRATION: The study was registered in the Current Controlled Trials database under the reference ISRCTN81286286.

Methodologies for the quantitative estimation of toxicant dose to cigarette smokers using physical, chemical and bioanalytical data.

Methodologies have been developed, described and demonstrated that convert mouth exposure estimates of cigarette smoke constituents to dose by accounting for smoke spilled from the mouth prior to inhalation (mouth-spill (MS)) and the respiratory retention (RR) during the inhalation cycle. The methodologies are applicable to just about any chemical compound in cigarette smoke that can be measured analytically and can be used with ambulatory population studies. Conversion of exposure to dose improves the relevancy for risk assessment paradigms. Except for urinary nicotine plus metabolites, biomarkers generally do not provide quantitative exposure or dose estimates. In addition, many smoke constituents have no reliable biomarkers. We describe methods to estimate the RR of chemical compounds in smoke based on their vapor pressure (VP) and to estimate the MS for a given subject. Data from two clinical studies were used to demonstrate dose estimation for 13 compounds, of which only 3 have urinary biomarkers. Compounds with VP > 10(-5) Pa generally have RRs of 88% or greater, which do not vary appreciably with inhalation volume (IV). Compounds with VP < 10(-7) Pa generally have RRs dependent on IV and lung exposure time. For MS, mean subject values from both studies were slightly greater than 30%. For constituents with urinary biomarkers, correlations with the calculated dose were significantly improved over correlations with mouth exposure. Of toxicological importance is that the dose correlations provide an estimate of the metabolic conversion of a constituent to its respective biomarker.

Changes in levels of biomarkers of exposure observed in a controlled study of smokers switched from conventional to reduced toxicant prototype cigarettes.

UNLABELLED: Reduced toxicant prototype (RTP) cigarettes with substantially reduced levels of tobacco smoke toxicants have been developed. Evaluation of these prototype cigarettes included measurement of biomarkers of exposure (BoE) to toxicants in smokers switched from conventional cigarettes to the RTPs. A 6-week single-blinded randomised controlled study with occasional clinical confinement was conducted ( TRIAL REGISTRATION: ISRCTN7215735). All smoking subjects smoked a conventional cigarette for 2-weeks. Control groups continued to smoke the conventional cigarette while test groups switched to one of three RTP designs. Clinical confinement and additional assessments were performed for all smoking groups after 2 and 4-weeks. A non-smoker group provided background levels of BoE. On average, smokers switched to RTPs with reduced machine yields of toxicants had reduced levels of corresponding BoEs. For vapour phase toxicants such as acrolein and 1,3-butadiene reductions of ⩾70% were observed both in smoke chemistry and BoEs. Reductions in particulate phase toxicants such as tobacco-specific nitrosamines, aromatic amines and polyaromatic hydrocarbons depended upon the technologies used, but were in some cases ⩾80% although some increases in other particulate phase toxicants were observed. However, reductions in BoEs demonstrate that it is possible to produce prototype cigarettes that reduce exposure to toxicants in short-term use.

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.