Product Design
The Subjective and Electrophysiological Effects of Smoking Cigarettes with Constant Tar But Varying Nicotine Levels
Abstract
Describes a protocol for measuring the subjectives and pattern reversal-evoked potentials [PREP] of human subjects smoking cigarettes with constant tar but varying levels of nicotine.
Fields
- Notes
Draft material with marginalia.
- Hypothesis
- Inhalation ProfileAre cigarettes designed to cater to individual inhalation profiles?
- Low-yield cigarettes
Modification of low yield products to assure that adequate levels of nicotine delivery are maintained, and effects of yield changes on toxicity and dependence.- Measuring human intake
Development of scientifically valid procedures for measuring tar and nicotine levels that more accurately reflect human intake.- Nicotine transport, transfer, and uptake
Design changes which alter nicotine delivery or effect how the product causes and maintains dependence, including transfer of nicotine from tobacco to smoke, and uptake into the body.- Use of tobacco processing/ blends
Modification of tobacco products through changes in tobacco processing and use of blends, and measuring effects on dependence, behavior, and toxicity.- Neurobiology
- Sensory effects
Technologies used to measure, control, or alter sensory effects - Low-yield cigarettes
- Keyword
- Attribute perception ratings
- Brain activity
- Central nervous system (CNS)
- Consumer acceptability (Consumer preference)
- Electrophysiological
- Flavor/ Taste (Attribute measure)
- Human testing
- Nicotine delivery (Smoke nicotine or nicotine yield)
- Puff count
- Puff interval (Time between puffs)
- Puffing behavior (Human puff parameters)
- Satisfaction
- Sensory response
- Smoothness/Harshness (Attribute measure)
- Tar/Nicotine ratio (Nicotine/Tar Ratio or T/N ratio)
- Tobacco taste (Attribute measure)
- Total particulate matter (TPM or Tar)
- toxicology
- Brain activity
- Smoke Constituent
- Alkaloids
- Nicotine
- Total particulate matter
- Nicotine
- Named Organization
- Aamazing Technologies
- BGA Institut Fur Arzneimittel
- Council for International Organization of Medical Sciences
- Grass Instruments
- INBIFO, Intitut Fur Biologische Forschung (Philip Morris' secret biological research lab in Europe)
"INBIFO" stands for Institut Fur Biologische Forschung, or Institute for Biological Research. It is located in Germany. Philip Morris acquired Inbifo on June 30, 1971. Its stated mission was "quantitative biological product evaluation" by using "comprehensive toxicological and physiological testing. Major activities are listed as: product evaluation and modifications, product ingredients and ETS-related technical knowledge and smoke components. Inhalation toxicology was a key feature of Inbifo. (Derived from Bates No. 2505235055/5088)- Marian Zalis Debardeleben
- Maridon
- Neurosoft
- Storage Dimensions
- Technischer Uberwachungsverein Rheinland, Kohn
- World Medical Association
- BGA Institut Fur Arzneimittel
- Subject
- CNS/Brain (Effects)
- Sensory Effects—Taste (Effects)
- Smoke Constituents
- Smoke Nicotine (Measures)
- Smoothness/Harshness (Effects)
- T/N Ratios (Measures)
- Tar (Measures)
- Test/Consumer Preference (Testing)
- Sensory Effects—Taste (Effects)
Document Images
PROTOCOL P 0500/3203 930827 PAGE 10
3.6 Toxicology
As the test cigarettes correspond to commercially available
cigarettes, no additional toxicological risks are associated with
their smoking. Detailed information on the composition of the test
cigarettes, as it is given in appendix 3, was deposited at the BGA
Institut fur Arzneimittel and is registered under the number ...
(see APPENDIX 5).
3.7 Safety of Experimental Cigarettes
The cigarettes are made from normal American blend tobacco without
any additional ingredients. Even erroneous mixtures of tobaccos
will lead to cigarettes with compositions of ingredients within
the normal range. The CO2 extraction process does not leave any
residues and is well established and widely used also in food
processing.
The subjects will be continuously observed during and immediately
after smoking. If adverse effects (e.g., perspiration, vertigo,
nausea) are noticed, the test session will be halted and the study
physician will be summoned immediately.
3.8 Treatment of Adverse Effects
For adverse effects, treatment will be mainly symptomatic. For
cases of emergency, oxygen supply, atropine, pressors, vasocon-
strictors, and anticonvulsants will be held ready. In case of
strong adverse effects the subject will remain under medical
treatment and care until the effects will have disappeared.
.. . ~. .
PROTOCOL P 0500/3203 930827 PAGE 11
3.9 Study Design
A completely randomized factorial design will be employed where
(on different occasions) each subject will smoke each of the
cigarette types. Order of smoking will be randomized for each sub-
ject using established randomization procedures. The study will be
conducted double blind where neither the subjects nor the inves-
tigators are informed as to which test cigarette is being smoked
in a given test session.
3.10 Study Chronology
Prior to initial testing, subjects will be trained in using the
descriptive ballot and the controlled smoking procedure (7 puffs
per cigarette, see Appendix 6). This will be accomplished by smok-
ing 2 cigarettes which greatly differ in nicotine delivery.
For each test session, subjects will be scheduled by telephone at
least 24 h in advance. They will first be asked whether they have
any illnesses or are taking any medications which could preclude
testing. These illnesses and medications would include, but not be
limited to, influenza, colds, visual disturbances, medicines that
affect concentration or vision.
When it is concluded that testing is possible, a date and time
will be set and the subjects will be told to report to the in-
stitute 2 h prior to testing to ensure that they refrain from
nicotine and caffeine use.
Once subjects report for testing, they will be asked about com-
pliance to the deprivation requirements and once again asked about
health or medications that would preclude testing on that day.
Subjects will then be prepared for testing.
PROTOCOL P 0500/3203 930827 PAGE 12
3.11 Descriptive Ballot
After smoking each test cigarette, subjects will be required to
fill out a ballot, evaluating the cigarette on 7 variables (see
sample ballot in Appendix 7). Each variable will be rated on a
scale between 1 and 7. Four of the variables relate to cigarette
<flavop while the other 3 evaluate satisfaction, acceptability, and
concentration.
3,12. Pattern Reversal-Evoked Potentials
3.12.1 Instrumentation
A 30-cm (diagonal measurement) video monitor (AAmazing
Technologies Corp.) will be used to display the checkerboard pat-
tern which will be used as the stimulus for PREP recording. The
checkerboard pattern will be generated using a Neuroscan software
program (Neurosoft, Inc.) designed for that purpose.
PREPs will be. recorded using Grass Instruments A.C. amplifiers
(model 12A5). Low frequency filters will be set at 1.0 Hz and high'-ji
fi?'e"quency filters will be set at 1.0 KHz. Analogue to digital con-
version will be accomplished using a NeurosGan. .12-Bit A/D
converter (Neurosoft Corp.) at a digitization rate qf 1280 Hz and
at a sample duration of 200 ms.
The digitized PREP waveforms will be processed by a personal com-
puter using a Neuroscan (Version 1.0) data acquisition system
(Neurosoft Corp.). At the end of an experimental session, data
will be transferped to optical disk (Storage Dimensions, Inc.) for
off-line processing.
•f
PROTOCOL P 0500/3203 930827 PAGE 13
3.12.2 PREP acquisition
9-mm gold disc electrodes will be positioned over scalp locations
O1, 021 0Z, FP, and CZ (Jasper, 1958) and affixed with collodion.
A 6th electrode will be affixed to the forehead and serve as
ground. After the electrodes have been affixed, they will be
' a_.
filled with a conducting solution (i.e., electrolyte). Electrode
impedances will then be checked and the scalp under the electrodes
abraded slightly, if necessary, to achieve impedances under 5 Ka.
O1, 02 and OZ, and FP will serve as recording electrodes, while CZ
will.serve as the reference electrode.
The subjects will sit in a 40-m3 testing chamber, under dim il-
lumination, 1.0 m in front of a video monitor. Subjects will be
asked to focus on and count changes in color of a dot which will
appear in the center of the screen at the beginning of the record-
ing session. Once the session begins, a black and white
checkerboard pattern with 10 checks down and 10 checks across will
be displayed by the monitor. The dimension of each check of the
display will be 2.3 cm2. The black and white checks will reverse
positions at a rate of 2/s. Each reversal will trigger the data
acquisition system to sample a 200 ms epoch of the EEG. One
hundred and fifty epochs will be acquired in this fashion and will
constitute the presmoking baseline. _
Subjects will then be required to smoke one of the cigarettes
using a controlled smoking procedure (see APPENDIX 4) where number
of puffs, interpuff interval and manner of puffing are specified.
Immediately after extinguishing the cigarette, the subjects will
once again focus on the video monitor and PREPs will be recorded
in an identical manner as they were prior to smoking.
Following the postsmoking PREP recording, subjects will rate the
cigarettes using the descriptive ballot. The electrodes will then
be removed from the subjects scalp using an acetone free collodion
remover (Maridon Corporation) and the subjects will be free to
PROTOCOL P 0500/3203 930827
PAGE 14
l/~~'~-~~•~' -
leave the laboratory. This chronology of events will occur until
each of the subjects has smoked, on different occasions, all of
the cigarette types used in the investigation.
PREPs collected during a given test session will initially be
stored on virtual disk. After that, the PREPs will be transferred
to optical laser disk for long-term'storage.
Upon retrieval from storage,, the waveforms will be inspected for
(band pass, high pass = 1.0 Hz, low pass = 40 Hz). Following fil-
artefacts (e.g., muscle co`ntaEJ5&tI'6^_n) and digitally filtered
tering waveform baseline corrections will be performed and the
responses will be averaged. Averaged responses will be txans.f.erred4
tp.aaa=J-_di-sk for waveform measurement.
N2(130-150 ms.). Latency values will bederived for each peak by
for each averaged waveform. The 4 peaks, together with their nor-
mal latency ranges, are: Po(40-60 ms), N1(60-80 ms), P1(90-110ms),
Four peak latencies and 3,peak to peak amplitudes will be obtained
determining maximal amplitudes within the specified latency ranges
for the peaks. Each peak to peak amplitude value will be derived
by measuring the amplitude from the peak of one component to the
peak of the adjacent component. The measured values will be
evaluated statistically.
Ballot: Single factor (cigarette)-repeated measures ANOVAs
(Keppel, 1973) will be performed for each of the seven descriptors
PROTOCOL P 0500/3203 930827 PAGE 15
on the ballot. p-values of 0.05 or lower will be considered as
statistically significant. Post-hoc tests (Duncan's Multiple
Range) (Keppel, 1973) will be performed where appropriate.
PREP: Each latency and amplitude measure will be analyzed by a
separate 2-factor repeated measures analysis of variance (ANOVA).
The within subject factors will be condition (pre- vs postsmoking)
and treatment (cigarette), and the treatment x condition interac-
tion. Factors will be considered statistically significant if they
achieve a p-value of 0.05 or lower. Greenhouse-Geisser-corrected
values will be used where appropriate to account for the non-
independence of measures (Keppel, 1973). The ANOVA will be
followed by post-hoc (Duncan's Multiple Range) tests where ap-
propriate.
PROTOCOL P 0500/3203 930827 PAGE 16
4 SAFETY CONSIDERATIONS
The testing chamber will be equipped with a window so that the
subjects will be under continuous visual observation at all times
during testing. In addition, the chamber will be equipped with a
passive audio communications system so that the subjects will be
in voice contact with the experimenters throughout the testing. An
on-site physician will be called immediately if the subject re-
quests medical assistance or if the experimenters suspect that
such assistance is required. In addition, the subjects will be re-
quired to be checked by the attending physician prior to leaving
the Institute at the end of a test session.
For good hygienic conditions, all electrodes and other implements
that have come in contact with the subjects will be cleaned after
use. Cleaning will consist of washing the electrodes and imple-
ments in soap and water, followed by soaking in a disinfectant
solution. The experimenters will wash their hands with disinfec-
tant soap and water after each experiment.
To insure electrical safety, the EEG equippment is certified by
the Technischer Oberwachungsverein Rheinland, Koln (TOV).
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5 STUDY ORGANIZATION AND RESPONSIBILITIES
5.1 Study Organization
The study shall be performed at INBIFO Institut fRr biologische
Forschung, FuggerstraRe 3, D-51149 Koln.
Following units at INBIFO are involved in this study: Sensory
Physiology (SP) and Information Systems (IS). The performance of
the methods is in the responsibility of the respective team
manager.
Date of assays: ...
Name and Address of the
Clinical Study Director:
5.2 Responsibilities
Attending Physician: ............. ...........................
Date Dr.med. Dr.rer.nat. K. von Holt
Physician and Physicist
(Arzt und Diplomphysiker)
Sensory Physiology: ............. ...........................
Date Dr. F.P. Gullotta
Ph.D., Experimental
Psychologist
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PAGE 18
Information Systems: ............. ..........................
Date Dr.rer.nat. W. Gomm
Mathematician
(Diplommathematiker)
General Manager;
Dr.rer.nat.•W.•Reininghaus•
Date
.............
Physicist (Diplomphysiker)
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6 STORAGE OF MATERIALS AND RECORDS
Records will be stored in our archives for at least 30 years after
delivery of the final report to the client (SOP QA 10). Samples of
the cigarettes will be stored in our archives as long as their
quality under state-of-the-art storage conditions allows further
evaluation, but not longer than 30 years (SOP QA 11). All records
and samples can be claimed by the client.
