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' THIS REPORT IS CONFIDENTIAL TO THE BUSINESS OF THE COMPANYt IT SHOULD BE CAREFULLY HANDLED, IS NOT TRANSFfAAeLE TO ANOTHER INDIVIDUAL, AND IS NOT TO BE PHOTOCOPIED. If th. report has served Its purpose and is no longer needed, please rsturn It Inesdiatsly to the Central File at the Research Center for r.cord keeping purposes and d.strucrtfon. h. Accession Number: 82-194 Copy Number: Issued To: .7. .L• C6rlcs HILIP MORRIS U.S.A. ~ ~ .. RESEARCH CENTER . CHARGE NO- & TITLE: Behavioral Research - 1600 TYPE REPORT: ® ANNUAL ~`;,0 SEMIANNUAL ~ Q COMPLETION n SPECIAL . ., . . ..,,,_;, .;. . DATE: July 19, 1982 ''•PERIOD COVERED: July 1981 - July 1982 REPORT TITLE: Behavioral Research Laboratory Annual Report - Part II BY APPROVED BY DISTRIBUTION: M. Hausermann J. L. Charles J. E. Wickham A. I. Palmer R. F. -W. L. T. B. E. A. F. S. Seligman Resnik Farone Meyer Osdene F. P. A. D. B. L. N. J. B. J. Daylor Gauvin Kassman Knudson Kosakowski W. W. R. R. R. F. Claflin L. Dunn Fagan M. Ikeda D. Carpenter T. T. Goodale H. Gaisch F. Wi 11 H. Merrit A. C. Lilly R. L. P. D. N. R. A. A. Thomson Turano Eichorn Lowitz W. W. F. R. F. F. M. M. Kuhn Mutter Watson Waugh R. A. G. M. Jenkins Kallianos Keritsis A. Manzelli V. DeNoble F. Gullotta F. Ryan P. Mele_. j K. S. Burns J. F. Whidby H. L. Spielberg R. Morgan N CD O N O KEYWORDS: smoke inhalation, inhalation volume i'nspiratory time , , mean inspiratory flow, puff parameter analyzer, puff recorder, inhalation duration, nicotine retention, puff parameters, nicotine delivery e

TABLE OF CONTENTS ABSTRACT COMPLETED STUDIES BASELINE SMOKE INHALATION BEHAVIOR .................................. PAGE 1 CHANGES IN SMOKE INHALATION PARAMETERS .............................. 10 AS A FUNCTION OF NICOTINE DELIVERY - .FULL SCALE STUDIES IN PROGRESS INTERRELATIONSHIPS OF PUFFING DIMENSIONS . :......................... 26 INHALATION DIMENSIONS AND NICOTINE RETENTION INHALATION PATTERNS ON MARKET BRANDS AND THEIR "LIGHT" VERSI'ONS..... 39 SUGGESTED RESEARCH DIRECTIONS CONTINUED RESEARCH ON INTERRELATIONSHIPS OF PUFFING DIMENSIONS, .... 41 INHALATION DIMENSIONS AND NICOTINE RETENTION SMOKE INHALATION PATTERNS AND OTHER SMOKE COMPONENTS ................ 41

ABSTRACT Over the past two years we have been developing a procedure for moni- toring _ . toring smoke inhalation behavior outside of the laboratory. Data from! six subjects smoking their own brand demonstrate 1) the wide range of smoke inhalation patterns across smokers, and 2) the replicability of a subject's individual pattern for periods of up to 10 months. In addition to showing the stability of a smoker's'pattern, the ambulatory monitoring instrumenta- tion is sensitive to changes in patterns as a function of changing nicotine delivery of the rod and varying cigarette acceptability. Data from three of five subjects show changes in inhalation parameters which support the nico- tine-titration hypothesis. One of the two remaining subjects altered the temporal spacing of inhalations to smoke the last two thirds of the high nicotine cigarette more slowly than the low. In collaboration with R. Morgan of the Analytical Research Division and K. Gunst of Development's Smoke Studies Project, we have developed a proce- dure for investigating the interrelationships of smoking parameters and nico- tine retention. We are interested in comparing nicotine delivered on a single puff with nicotine recovered following experimental manipulations of puff and inhalation behavior. Results from initial observations suggest that puff volume is the critical determinant of the amount of nicotine delivered to the smoker. We developed a procedure for sampling mainstream smoke from the actual rod on which the smoker is puffing to more accurately analyze for nicotine delivery. Subsequent research can now focus on smoke inhalation behavior to determine the critical parameters influencing nicotine retention.

COMPLETED STUDIES - Baseline Smoke Inhalation Behavior The questions of why people smoke cigarettes and how they smoke have received increasing attention in recent literature, due in part to technolog- ical advances that have-enabled more thorough and more accurate data collec- r .. , _ " tion. tion. 7',The measures of smoking behavior are no longer restricted to observa- , ~ tion of number of puffs per cigarette and number of cigarettes perday, but now include information on the puff parameters of volume, flow, and duration. What the smoker does with -the bolus of smoke taken into the mouth during .. . . . . . - . . ~ • Y. ' ~ .. puffing, however, is a question that has only begun to be addressed. For many investigators the inhalation of tobacco smoke is a behavior which is referred to "in a broad sense" meaning "the intake of tobacco smoke f rom a cigarette including contributions from the number of puffs, puff volume, and the depth to. which smoke is inspired into the lungs" (Wald et al., 1980). We define smoke inhalation as a behavior distinctive from puf- fing, where the bolus of smoke-air mixture is taken from the mouth and drawn into the lungs. The few observations of smoke inhalation behavior reported in the literature have been based on short-term measurements obtained from hard-wired subjects confined'to the laboratory (Rawbone et al., 1970; Adams et al., 1981). Data collected under such controlled experimental conditions are probably not representative of normal smoke inhalation behavior. Over the past two years we have been developing a procedure which permits relatively unobtrusive monitoring of cigarette smoke inhalation across several hours as subjects smoke ad lib outside of the laboratory. Because this is a new procedure, we have concentrated on examining baseline

data as subjects smoke their usual brand of cigarette. We were initially interested in two fundamental questions: 1) What measures of smoke inhala- tion would be most useful in describing the behavior; and .2) Can an individ- ual's inhalation behavior be characterized in terms of a reproducible pat- tern. Using the smoke inhalation patterns obtained from two subjects, we determined that smoke inhalations could be represented by these measures: 1 volume, 2) inspiratory time, 3) mean inspiratory flow, 4) "retention" time or plateau of the inhalation curve, 5) duration of the inhalation-exhalation cycle, 6) time between inhalations, and 7) time between cigarettes. We'are also recording number of puffs per cigarette and number of cigarettes smoked . .~ r.. , . . during the monitoring period. . ';, __... We have analyzed inhalation recordings in terms of these parameters to provide basic information on smoke inhalation behavior, such as: 1) The degree of behavioral stability on each inhalation measure (vol- ume, inspiratory time, flow, etc.) that can be achieved from long- term ambulatory monitoring of the smoker. 2) The typical point in the monitoring period at which the smoker ha- bituates to the instrumentation. 3) The point at which the behavior restabilizes following a change to a new cigarette. The results are being used to establish a criterion for stability of the inhalation pattern under baseline smoking conditions. Future research ex- amining changes in inhalation parameters under various experimental manipula- tions would yield results based only on differences in stable behaviors, excluding measures of general disruption.

Method Six R&D employees, five male and one female, served as subjects. The smokers' usual brands were: Merit Regular 85 (N=2), Merit Regular 100 (N=1), Benson & Hedges Lights Menthol (N=1), Benson & Hedges Regular (N=1), and Marlboro 100 (N=1). Subjects were suited shortly after they arrived ,.:4 with the inhalation monitoring instrumentation ,~,._.. __. . ...... . at work. The ambulatory system consists of two Respiband" transducers which the smoker wears around his rib cage and abdo- men, an oscillator providing current to the Respiband coils, an interface for processing changes in inductance of the coils as the subject inhales and exhales, and a miniature cassette recorder which can record 24 hours of res- piratory piratory information. A puff detector has been added to the recording system to enable rapid and reliable distinction between smoke inhalations and normal respiration and movement. A block diagram of the system appears in Figure 1. (For a detailed description of the ambulatory monitoring system refer to the Behavioral Research Laboratory Annual Report, 1980, Part II). Following hook-up subjects were calibrated for positioning of the coils on the torso. This involved measuring the relative contributions of rib cage and abdomen to the total volume in two positions - standing and supine. Subjects wore the ambulatory instrumentation back to their normal work setting, and every res- piration was recorded on the cassette tape. Approximately three hours later the smokers returned to the laboratory for a calibration check. System accuracy was assessed by applying the morning calibration values to the rib cage and abdominal deflections made while the subject breathed a known volume of air. Accuracy was determined by comparing the measured inhalation volumes with the known volume of the referent. New calibration factors were then obtained to correct for slight slippage of the coils on the torso that would

, Oscillator . Subject -----~ I Respitracefi'' Transducer . Respitrace Interface Puff' Detector Medilog Recorder ~. . -1 Figure 1. Block diagram of inhalation nranitoring' systPSn ; 9Z064ZEOOZ 1 1. Playback Unit MIlM/DF]CLAB 2 .

distort the data. Subjects again reported back to their work setting until the end of the day, at which time a second calibration check was made and the instrumentation was unhooked. A repeated measures design was used to examine stability of a subject's indi'vidual inhalation pattern over successive measurements. Recordings have been collected from these six smokers across six week (N=4), nine week (N=1) and ten month (N=1) periods. „ . .. r..,<-. ~L.IC,:i, uata Anai,yses 'C,`=. . ~ f A dedicated MINC/DECLAB 23 minicomputer, programmed by F. Ryan, was used to perform data interpretation and analyses. Each three hour block of respi- ration data was replayed from the cassette tape into the minicomputer and was digitized. Calibration factors were applied to the rib cage and abdominal signals and the data was summed to a total volume. The computer searched for each puff detector signal and displayed the graphic data of that puff-inhala- tion cycle on the screen.. The experimenter scrolled through the inhalation data, placing cursors at the points which would .numerically represent each pattern in the data file. Means and standard errors of the dependent meas- ures were determined across cigarettes and across days. Results System;Accuracy System accuracy has been shown to be >95.5% in the ability to measure a volume identical to the known referent for over 200 two- to five-hour ses- sions. The calibration factors obtained at the beginning of the session remain representative of the positioning of the coils on the subject follow- ing several hours of normal physical activity. -5-

Smoke-Laden Inhalation Behavior Results from repeated measures on six subjects smoking their own brand show that there are a large range in inhalation behavior which a smoker will demonstrate from one inhalation to the next. The inhalation pattern is not a fixed behavior that is automatically executed in the same way following every puff. In spite of thi s range of i nhal ati on behavi or there appears to be a. characteristic pattern that can be determined for each individual smoker on his own brand of cigarette. There is a reproducible daily mean for volume, inspiratory time, mean flow rate and duration. Habituation to the instrumen- tation appears to occur during the first monitoring session for all subjects, where means for day 1 have been shown to be different from day 2, falling outside of the range of all means on subsequent days. Data from the first day will, therefore, be excluded from all analyses. The mean values for volume, inspiratory time, mean flow rate, duration and number of puffs per cigarette have been shown to be fairly consistent (<±16% range for each variable) across days for periods of up to 10 months (Table 1). This level of stability in the baseline behavior is achieved following interruptions of time, such as when the subject goes on vacation, and interruptions of brand switching, where the subject is monitored as he returns to his usual brand of cigarette. After the first day of habituation to the instrumentation, the stability in baseline measures from cigarette to cigarette does not improve with successive monitoring periods. Those sub- jects who demonstrate large variability in the average values for any of the dependent measures will continue to show large variability in these measures across all monitoring periods and, conversely, those subjects who demonstrate more stable behavior will continue to show stability in these measures across successive days. We will, therefore, be including data from all but the first day in our analyses.

Tabl e 1 Range of Daily Means for Smoke Inhalation Parameters Mean ` Yolume S1 ±10.0% S2 ".t14.7% S3 ±10.8% S4 ± 6.3% S6 ±14.0% S7 ± 6.5% Inspiratory I Time ±11.2Z ±10.4% ± 7.7% ± 9.7% ± 2.7% ± 3.7% J...._. ~ . . . . ~ 7 `+ . ... . Inspi ratory Flow ,. Retention Time t35.1% ±33.3% ±35.2% t31. 0% ±22.5% ±22.5% Duration ±13.9% ±12.6% t15.9% ± 9.1% ± 2.9% ± 4.6% The dependent measure of retention time is highly variable both~within a day and across days. Subjects will vary their retention time from zero or no retention - when inhalation stops, exhalation immediately begins - to a retention of several seconds. Determination of when exhalation actually begins is the most difficult point for the experimenter to identify on the inhalation-exhalation curve, which may also contribute to the variability in the retention time measure. Although not a parameter of inhalation behavior, the measure of time between inhalations also shows large variability - a result of clustering of puffs on some cigarettes in addition to the more even spacing of puffs on other cigarettes. The absence of trend on all of the inhalation measures across an exten- ded moni'toring period suggests that there are no baseline shifts to be taken into account in subsequent research. We can obtain an average measure for each variable across all of the inhalations to demonstrate the smoker's typi- cal pattern under a given smoking condition.