Smoking Topography Study 2018

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. We 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.

That we found no differences in smoking topography of cigarettes smoked over
the day means that in this new study, we can invite participants for a shorter
time because we only need data of 4 cigarettes to model their profile needed
for exposure measurements. The smoking topography parameters are needed for the
settings of a smoking machine whereby the exact exposure to cigarette smoke
toxicants can be determined.

In the last study we 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 a small puff volume, possible followed by different exposure in
the lungs.
In this new study we want to measure the respiratory parameters of breathing
and inhalation over the day. Until now, inhalation risk assessment is based on
human breathing patterns, while breathing and inhaling smoke are not the same
due to the composition of the smoke containing harsh compounds. The current
study aims at measuring respiratory parameters to identify the lung
compartments exposure related to smoking topography. This can be achieved by
respiratory inductive plethysmography (RIP), a non-invasive device that can be
worn throughout the day. The Hexoskin is a known non-invasive device for
measuring RIP, and will be worn by the smokers all day.

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 responsible for part of the smoke composition. We are
interested in how smoking behavior and inhalation, and thus exposure, changes
when offering a Marlboro smoker another sort of cigarette.
Therefore, we are interested whether the smoking behavior changes when the
smoker has to smoke the Marlboro Prime, a low TNCO cigarette. 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 not diluted with sidestream 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.

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. As the
participants receive the Marlboro Prime so that they can smoke at home, they
can get used to it and develop *natural* smoking behavior.

As during the last study, the sampling is following a sampling scheme. 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 will be
mimicked with machine smoking experiments, which results in the exact exposure
for that person. 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, because of using the CRESS. They all *practiced* smoking with
the CRESS the evening before the experimental day. In the present study we will
invite 2 smokers 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.

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

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 cotinine levels in blood/urine changing over the day and
connected to the smoking behavior of the different cigarettes?

The Smoking Topography Study 2018 is a prospective observational study, 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.
An experimental day starts at 08.00hr and ends at 19.00hr. The different
studydays have exactly the same set-up, only the cigarette brand smoked during
the different days is different.
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, we have to measure the smoking 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.

Participants are their own control by measuring baseline samples (t=baseline).
This sampling takes place upon arrival, before the first cigarette is smoked.
Participants are asked not to smoke when waking up, but to wait upon their
arrival at the research location. These baseline samplings include urine,
exhaled air, blood, 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. 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, we make use of experimental time. 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 moth swap is collected at t=baseline, and at 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, we
have made 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 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.

Not applicable

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.