Alison Eldridge

Variation in tobacco and mainstream smoke toxicant yields from selected commercial cigarette products.

There is a drive toward the mandated lowering and reporting of selected toxicants in tobacco smoke. Several studies have quantified the mainstream cigarette emissions of toxicants, providing benchmark levels. Few, however, have examined how measured toxicant levels within a single product vary over time due to natural variation in the tobacco, manufacturing and measurement. In a single centre analysis, key toxicants were measured in the tobacco blend and smoke of 3R4F reference cigarette and three commercial products, each sampled monthly for 10 months. For most analytes, monthly variation was low (coefficient of variation <15%); but higher (⩾ 20%) for some compounds present at low (ppb) levels. Reporting toxicant emissions as a ratio to nicotine increased the monthly variation of the 9 analytes proposed for mandated lowering, by 1-2 percentage points. Variation in toxicant levels was generally 1.5-1.7-fold higher in commercial cigarettes compared with 3R4F over the 10-month period, but increased up to 3.5-fold for analytes measured at ppb level. The potential error (2CV) associated with single-point-in-time sampling averaged ∼ 20%. Together, these data demonstrate that measurement of emissions from commercial cigarettes is associated with considerable variation for low-level toxicants. This variation would increase if the analyses were conducted in more than one laboratory.

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 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

BackgroundDespite 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/designThis 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.DiscussionData 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 registrationThe study was registered in the Current Controlled Trials database under the reference ISRCTN81286286.

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.

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.

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.

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

&NA; 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 TobRegs stated aims. HighlightsWHO TobReg proposals to reduce levels of 9 cigarette smoke toxicants were tested.All available (80–97%) cigarette products from 4 diverse countries were analysed.70–100% of cigarette products failed to meet the proposed WHO regulatory models.These proposals would have greater impact on global markets than WHOs stated aims.

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

Abstract 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.

Influence of cigarette circumference on smoke chemistry, biological activity, and smoking behaviour.

Cigarettes with reduced circumference are increasingly popular in some countries, hence it is important to understand the effects of circumference reduction on their burning behaviour, smoke chemistry and bioactivity. Reducing circumference reduces tobacco mass burn rate, puff count and static burn time, and increases draw resistance and rod length burned during puff and smoulder periods. Smoulder temperature increases with decreasing circumference, but with no discernible effect on cigarette ignition propensity during a standard test. At constant packing density, mainstream (MS) and sidestream (SS) tar and nicotine yields decrease approximately linearly with decreasing circumference, as do the majority of smoke toxicants. However, volatile aldehydes, particularly formaldehyde, show a distinctly non-linear relationship with circumference and increases in the ratios of aldehydes to tar and nicotine have been observed as the circumference decreases. Mutagenic, cytotoxic and tumorigenic specific activities of smoke condensates (i.e. per unit weight of condensate) decrease as circumference decreases. Recent studies suggest that there is no statistical difference in mouth-level exposure to tar and nicotine among smokers of cigarettes with different circumferences. Commercially available slim cigarettes usually have changes in other cigarette design features compared with cigarettes with standard circumference, so it is difficult to isolate the effect of circumference on the properties of commercial products. However, available data shows that changes in cigarette circumference offer no discernible change to the harm associated with smoking.

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

Abstract 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.