Smoking Topography Study 2018
Smoking Topography Study 2018
Rationale: The World Health Organization Framework Convention on Tobacco Control (WHO FCTC)
 aims for a regulatory strategy including the regulation of the contents of tobacco products
 (Article 9). Cigarette smoke includes more than 7000 chemicals which are harmful and cause
 tobacco-related diseases. In the future, regulation of these harmful cigarette constituents
 should be based on more chemical classes, as the WHO suggested. However, in order to
 introduce such class-based regulation, a scientific base is needed to define upper limits of
 allowed amounts of chemicals (groups) in cigarette smoke emissions and to ensure decreased
 harmful health effects due to cigarette smoking. To date, the causality between human
 exposure to specific cigarette smoke compounds and the harmful effects is unknown. The first
 step in closing the gap in knowledge between cigarette smoke exposure and developing
 tobacco-related diseases includes a proper determination of human exposure to cigarette smoke
 chemicals. This includes measuring smoking topography and inhalation. Smoking topography is
 how the smoker smokes the cigarette (puff volume, duration, flow etc). The goal is to link
 smoking behavior to smoke exposure, for 2 different cigarette brands. The participants will
 smoke their 'normal' brand Marlboro (experimental day 1) after which they receive the low
 TNCO (tar, nicotine and carbon monoxide) Marlboro Prime to smoke at home. A week later the
 experimental day (day 2) is repeated with this cigarette. On the last experimental day (day
 3), the participants will smoke the Prime cigarette while the ventilation holes of this
 low-TNCO cigarette are taped. Afterwards, the personal smoking profiles of the participants,
 and thus their individual exposures, will be mimicked in the lab using machine smoking. The
 observed smoking topography and inhalation parameters together give information about the
 exposure to smoke toxicants. In addition, this study is also designed to measure biomarkers
 of exposure in body fluids of smokers, such as nicotine and the most abundant cigarette smoke
 chemicals and their metabolites.

 Objective: We want to find out whether the individual habitudinal smoking topography of a
 smoker smoking his usual brand, and the changes between cigarettes over the day, can be
 compared to that of smoking a low-TNCO or high nicotine cigarette (i.e. the Marlboro Prime
 and Red Sun). In addition, differences in inhalation patterns are investigated. Next to that,
 the exposure will be connected to the nicotine and carbon monoxide levels in blood and/or
 urine. Also smoke toxicants (and metabolites) in exhaled air, saliva, urine and blood of
 smokers are determined.

 Study design: This prospective observational study monitors smokers in their habitudinal
 smoking during the day (for 10 hr) while smoking Marlboro, Marlboro Prime and Marlboro Prime
 taped cigarette, while during the day bodily fluids are sampled at several time points.

 Study population: This population consists of 18 Caucasian, healthy, adult males, aged
 between 25-34 years old. Participants should be used to smoke Marlboro (red/regular) for at
 least 3 years with a daily average of 13 to 25 cigarettes (about a package every day).

 Nature and extent of the burden and risks associated with participation, benefit and group
 relatedness: The participating smokers smoke according to their habitudinal smoking pattern,
 and are therefore not increasingly exposed to the harmful health effects of cigarette
 smoking. The invasive part of the study is their stay for 3 days (and 1 night when wanted) in
 a hotel, and the sampling of blood, saliva, urine and exhaled air.
In 2005, the World Health Organization Framework Convention on Tobacco Control (WHO FCTC) was
 established with the aim for a regulatory strategy as a response to the globalization of the
 tobacco epidemic. One of their non-price measures to reduce the demand for tobacco includes
 article 9: Regulation of the contents of tobacco products . Cigarette product regulation is
 currently based on tar, nicotine and carbon monoxide (TNCO) levels in cigarette smoke, which
 are indicated on the package. This is not sufficient, since cigarette smoke includes more
 than 7000 chemicals. There are aldehydes, VOCs, PAHs, nitrosamines, metals and so much more
 measured in cigarette, causing tobacco-related diseases .

 In the future, regulation of these harmful cigarette constituents should be based on more
 chemical classes, as the WHO suggested. However, in order to introduce such class-based
 regulation, a scientific base is needed to define upper limits of allowed amounts of
 chemicals (groups) in cigarette smoke emissions and to ensure decreased harmful effects due
 to cigarette smoking. To date, the causality between human exposure to specific cigarette
 smoke compounds and the harmful effects is unknown. The first step in closing the gap in
 knowledge between cigarette smoke exposure and developing tobacco-related diseases includes a
 proper determination of human exposure to cigarette smoke chemicals.

 Unfortunately, there is a lack of methodology to determine cigarette smoke exposure in humans
 .

 In a prospective observational pilot study in February 2016, natural human smoking behavior
 was characterized: Smoking Topography Study 2016 (NL55676.068.15). The smoking topography of
 every smoked Marlboro cigarette was monitored through the CRESSmicro device, which records
 the puff length, the puff interval, the puff flow and the puff volume. In this study, the
 investigators could model the individual smoking profiles per participant by using data of 4
 random cigarettes. During modelling, puff volume, duration (and thus also flow) and interpuff
 interval were taken into account.

 Since there were no differences in smoking topography of cigarettes smoked observed at
 different times of the day implies that in this new study, the researchers can invite
 participants for a shorter time because only data of 4 cigarettes is needed to adequately
 model their overall smoking profile needed for exposure measurements. These smoking
 topography parameters are needed for the settings of a smoking machine, applied to mimic the
 exact exposure to cigarette smoke toxicants for each individual.

 In our previous study the researchers concluded that smokers have their own individual
 smoking topography. Of course, smoking is also accompanied by the inhalation of harmful
 chemicals, but the smoker is not aware of this during smoking and therefore does not adapt
 his smoking topography with respect to that exposure. However, it is unknown by what means
 the individual smoking topography parameters are related to toxicant exposure in the
 different parts of the lungs. For example, higher puff volumes with a different composition
 of toxicants lead to a different inhalation pattern than small puff volumes, possible
 followed by different exposure in the lungs.

 In this new study the researchers want to include respiratory parameters of breathing and
 inhalation over the day as well. Until now, inhalation risk assessment is based on human
 breathing patterns, while breathing and inhaling smoke are not the same due to the presence
 of harsh compounds in the smoke. The current study aims to measure respiratory parameters to
 identify which lung compartments are exposed to what extent in relation to the observed
 smoking topography. This can be achieved by respiratory inductive plethysmography (RIP), a
 non-invasive device that can be worn throughout the day. In the current study, the Hexoskin
 will be applied for these measurements.

 Literature describes that the process of smoking topography and inhalation differs per
 cigarette and situation . In other words, the smoker doses himself to gain nicotine, with
 additional production of carbon monoxide (CO) and other harmful cigarette smoke-associated
 chemicals.

 As described before, in the future cigarettes will be changed as they are only allowed to
 contain a maximum of certain toxicants. One of the options to make cigarettes less addictive
 is to add less nicotine. It is known that smokers show compensating behavior when smoking
 other cigarettes than their used to, to gain the same amount of nicotine. Our machine smoking
 experiments show that when smoking low-TNCO cigarettes, the composition of the smoke per mg
 nicotine changes under the same smoking conditions. This means that the cigarette
 characteristics are also at least partly responsible for the smoke composition. The
 researchers are interested in how smoking behavior and inhalation, and thus exposure, changes
 when offering a smoker another type of cigarette.

 Therefore, the researchers are interested whether the smoking behavior changes when the
 smoker has to smoke a low TNCO cigarette, i.e. the Marlboro Prime. The low values of nicotine
 in the smoke of the Marlboro Prime are partly achieved by ventilation holes in the cigarette
 filter. By closing these filter vents with tape around the filter, the smoke is no longer
 diluted with side stream air, and the cigarette design is slightly different.

 The participants will smoke their 'normal' brand Marlboro (day 1). After the experimental
 day, they receive the Marlboro Prime for smoking at home, so they get used to smoking a 'new'
 cigarette. A week later the experimental day (day 2) is repeated with this cigarette. The
 participants can stay overnight, or come back the next day (day 3) to smoke the Prime
 cigarette while the ventilation holes of this low-TNCO cigarette are taped. See the scheme in
 Table 1.

 As in the STS2016, this study again is aimed at measuring smoking in a habitual rhythm
 without imposing it as has been done thus far , , . With this, the natural smoking topography
 per cigarette can be measured, in combination with the respiratory parameters by wearing a
 non-invasive RIP device. By providing the participants with the Marlboro Prime cigarettes
 prior to the experimental days 2 and 3, they can get used to smoking them at home in order to
 develop 'natural' smoking behavior.

 As during the last study, the sampling is following a sampling scheme (Figure 1). In summary,
 during the day, blood, exhaled air, urine and saliva will be sampled to measure nicotine,
 carbon monoxide, but also other cigarette smoke compounds, such as aldehydes and their
 metabolites.

 In the future, the personal smoking regimes of the participants, and thus their personal
 exposures, will be mimicked with machine smoking experiments. This will be linked to the RIP
 parameters.

 Points of attention that came out of the STS 2016, include that smokers smoked less
 cigarettes than expected. Reason for that is, as they mentioned, that they cannot smoke in
 the apartment, while they smoke inside at home. Another reason was that they have to smoke
 alone, while at home or work there often is a co-smoker. The participants didn't experience
 difficulties or changes in smoking behavior due to the use of CRESS. They all 'practiced'
 smoking with the CRESS the evening before the experimental day. In the present study 2
 smokers will be invited at the same time. Again, smokers have to go outside for a smoke to
 protect the researchers to secondhand smoke exposure. This is kept as attainable as possible.

 Primary Objective:

 Is there a difference in natural smoking topography between Marlboro, Marlboro Prime and
 Marlboro Prime taped leading to a different exposure for the smoker?

 Secondary Objective(s):

 Is it possible to map personal smoking profiles with only 4 random cigarettes, as showed in
 the previous Smoking Topography Study 2016?

 Is a different smoking topography profile per smoker related to deviating exposure of
 mainstream smoke in the respiratory tract compartments, for the different cigarettes?

 Can exhaled air of smokers be used as biomarker for exposure to VOCs/aldehydes?

 Are nicotine and toxicant (metabolite) levels in blood/urine changing over the day and
 connected to the smoking behavior of the different cigarettes?

 Study Design The Smoking Topography Study 2018 is a not-randomized cross-over study with a
 single group, with the duration of 3 months. Participants will visit our research apartment
 at Apart Hotel Randwyck, for 1 day in the first week and 2 days in the second week (Table 1).

 An experimental day starts at 08.00hr and ends at 19.00hr (Figure 1). The different study
 days have exactly the same set-up with the cigarette brand smoked during the day being the
 only difference. In this study it is important that the participants are able to smoke
 cigarettes 'ad libitum'. Because it is impossible to monitor this smoking topography at home,
 The smoking topography is measured at a research location. Therefore, this study takes place
 in an apartment at Hotel Randwyck in a homelike atmosphere where standardized meals are
 served and cigarettes can be smoked when and how the participant desires. The smoking
 topography of every smoked cigarette will be monitored through the CRESSmicro device, which
 records the puff length, the puff interval, the puff flow and the puff volume . Furthermore,
 the exact time point of smoking (i.e. the moment the cigarette is lit) is noted in the
 experiment time table.

 Due to this setup, the smoking topography measurements do not take place at scheduled time
 points and therefore only 2 participants per day will be measured. Total duration of the
 study will be 3 months, including 18 smoking individuals (Table 1).

 Participants are their own controls by measuring baseline samples (t=baseline). This sampling
 takes place upon arrival, before the first cigarette is smoked. Consequently, participants
 are asked not to smoke when waking up, but to wait upon their arrival at the research
 location. These baseline samplings include the collection of urine, exhaled air, blood, a
 mouth swap and saliva.

 Goal of a study day is to follow the smoker in his personal daily life smoking schedule. They
 can smoke when they want or feel the urge to smoke. Therefore, the sampling time points and
 the amount of cigarettes smoked are unknown per participant (Figure 1). Despite the unknown
 time points on forehand, smoking topography of every single cigarette within their presence
 at the research apartment is measured. During the whole experiment, experimental time is
 used. The start of the experiment (expected to be around 09.00hr) is the start of the
 experimental day, noted as timepoint 0. This is probably shortly after the baseline
 measurements.

 All spent cigarette butts are collected in separate plastic tubes per participant with the
 experimental smoking time noted. Because it is very important not to interfere with the daily
 life smoking schedule, the experiment day is divided into timeslots for urine and a fixed
 time point for saliva sampling.

 Urine will be collected at baseline and during 2 time periods. The first time point includes
 the baseline measurement before the first cigarette is smoked. Next, all urine between t=0
 and t=5 hours is collected in 1 beaker and urine between t=5 and t=10 is collected in another
 beaker. The participant is asked to empty his bladder just before the timeslots end. This
 results in 3 urine samples per participant.

 Saliva and a mouth swap are collected at t=baseline, t=0 (immediately after the first
 cigarette), t=5 and t=10. This results in 4 saliva samples and mouth swaps per participant.

 The exhaled air and blood samples are collected before and immediately after smoking a
 cigarette to have the most accurate measure associated with the cigarette smoking. However,
 the smoking time points are uncertain due to the chosen setup of this study. However, since
 all smokers included smoke around 20 cigarettes a day, they will at least smoke every 2 to
 2.5 hours. Therefore, time periods of 2.5 hours in which the first cigarette smoked is used
 for sampling blood and exhaled air, immediately after finishing smoking.

 At baseline, the participant is asked to exhale via the nosemouth cap of the Owlstone (a
 breathing device) whereby the exhaled air passes the adsorption tubes. The exhaled air just
 before and after finishing smoking the first cigarette is collected (t=0). The same is done
 for cigarettes smoked between t=2.5 and t=5, between t=5 and t=7.5, between t=7.5 and t=10
 and the last sampling at T=10. This results in 7 exhaled air samples per participant.

 To avoid multiple punctures, the participants get a peripheral venous canula at baseline,
 after which the baseline blood sample is withdrawn. The next blood sample is withdrawn just
 before and after finishing smoking the first cigarette (t=0). Then, the sampling points are
 just before and immediately after the first cigarette between t=0 and t=2.5, between t=2.5
 and t=5, between t=5 and t=7.5, between t=7.5 and t=10 and the last sampling is at T=10. For
 analysis of blood aldehydes an extra blood sample will be drawn from the canula at baseline
 and immediately after the first cigarette as well as immediately before and after the first
 cigarette after t=5 and t=7.5. This results in 13 blood sampling points per participant.
Inclusion Criteria:

 -  Male

 -  25-35 years old (birth year 1982 - 1992)

 -  Caucasian

 -  Smoking Marlboro as usual brand for at least 3 years

 -  Used to smoke between 13 and 25 cigarettes a day (around a package/day)

 Exclusion Criteria:

 -  Heavy smoker (minimum of 25 cigarettes/day)

 -  Smokes more than 1 brand on a regular base.

 -  Amount of cigarettes per day varies ±10, between days

 -  Daily medication use

 -  Experienced adverse effects due to smoking

 -  Suffering chronic illness