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Topical Report NCI/S&HP/ORNL #44 SITE VISIT VI TO VETERAN'S ADMINISTRATION HOSPITAL East Orange, New Jersey, May 2-3, 1977 7-20-77 B. E. Gill, R. B. Quincy, and R. A. Jenlcins Tobacco Smoke Research Program Bio/Organic Analysis Section Analytical Chemistry Division Oak Ridge National Laboratory Oak Ridge, Tennessee 37830 Interagency Agreement (ERaA-NIH/NCI) No. 40-485-74, Part II Internal (ORNL)<Contract Charge No. 3390-0224 Intended for informal communication with project management only. Confidential until published or released by author. ,

SITE VISIT VI TO VAH B. E. Gill, R. B. Quincy, and R. A. Jenkins Summar . Data gathered on our sixth site visit to the Veteran's Admin- istration Hospital, East Orange, NJ, indicate that the two animal groups are being offered two distinctly different doses of nicotine, but iden- tical total particulate matter doses. The magnitude of this dose is similar 'to that in other NCI-sponsored inhalation studies. Preliminary measurements of the carbon monoxide and carbon dioxide content of the smoke reaching the cannula exit indicate that the smoke dose which the animals receive is highly enriched in gas phase constituents. Detailed chemical analysis of the particulate phase of the smoke of the LN variant suggests that few particulate phase components are being se- lectively enriched or depleted during passage through the exposure devices. Introduction. A sixth site visit was made to the Veteran's Administration Hospital on May 2-3, 1977, to observe and document the beagle exposure study which is being conducted there. As has been the case on previous visits, our primary purpose was to collect data to enable us to better estimate the dose which the animals receive and to determine the extent to which certain smoking factors can contribute to the variability in that dose. Both exposure and experimental details have been previously discussed, and can be found in reports covering previous site visits (Topical Reports NCI/S&HP/ORNL #6, 17, 18, 31, 32, and 38). Experimental. In order to accomplish exposure definition, it has been necessary to obtain information concerning both the physical operating performance and smoke delivery performance of the ADL-I machines in service. In addition, we are directing our monitoring effort toward a more detailed chemical characterizatior of the smoke which the animals are offered. Many samples'of smoke generated from the Code LN variant (both ADL-I input and cannula exit samples) were returned and subjected to a multi-component, multi-aliquot analysis. In this process, several

key components of the smoke are analyzed, usually via gas chromatography. This permits a much more detailed chemical description of the particulate phase of the smoke, as several of these components correlate highly with the presence of entire classes of smoke constituents. As mentioned in 'the "Preliminary Observations, Site Visit VI..." (Topical Report #39), this was our first opportunity to sample, on site, the cannula exit for carbon monoxide (CO) and carbon dioxide (C02). CO is important because of its physiological impact, and the ratio of CO and CO2 contents of the smoke give an indication of the pyrolysis con- ditions in the burning cone of the cigarette. Briefly, the apparatus for obtaining a gas phase sample from the cannula exit is similar to that for a particulate phase sample, except that the effluent from the respir- ator (ventilator) is expelled into a large, evacuated Saran gas-sampling bag. Following completion of smoking, the contents of the bag are mixed thoroughly, and a small portion is drawn into a small glass gas sampling bulb. The bulb is then returned to ORNL for analysis, which is performed by gas chromatography using Amberlyst ion exchange resin in the Ni-form as the "stationary phase". Results and Conclusions. Table I lists the measured puffing parameters for the ADL-I machines in service at the time of our visit. In Ward 3, puff volumes were significantly low. This is not manifested in lowered smoke generation by those machines (see Table III). However, this effect can be masked by high cigarette-to-cigarette variability (see below). With the exception of Ward 3, when judged in terms of these puff parameter measurements, the operation and reliability of the machines continue to be adequate. Table II compares the static burn rate (in weight of cigarette burned per minute) of cigarettes smoked at VAH with that of those re- turned to ORNL and smoked under analytical conditions. The HN variant burns substantially faster, while the LN variant burns slightly faster at VAFi. This is probably due to the ventilation air flow across the cigarettes. Also, while on-site, we measured the relative humidity as fluctuating between 39% and 65%. A lower relative humidity can contribute

to higher static burn rates, which, in turn, can act to reduce the total amount of smoke generated by the machines. The deliveries of total particulate matter (TPM) and nicotine of cigarettes smoked on the ADL-I machines at VAH are tabulated individually on Table III. Examination of the data indicates a rather large variation in the amount of smoke generated for a given variant by the machines. Table IV compares the amount of smoke generated on-site with that gen- erated under analytical conditions (at three puffs per minute) at ORNL. The data indicates that the exposure devices generate somewhat less smoke on-site. A higher static burn rate could partially contribute to this lowered delivery on-site by consuming more of the cigarette during non-puffing fraction of the smoking cycle. The relative ratio of the nicotine content of the smoke of the two variants is somewhat lower than that observed analytically (2.6 vs 3.1). But the nicotine:TPM ratios of both exposure and analytical smokes for a given variant are essentially the same. This indicates that the smokes of the HN variant do not con- tain differing amounts of nicotine, but rather that the machine-HN variant combination produces less smoke on-site. Ultimately, this has an effect on the differences in the nicotine doses which the animals are offered. Table V tabulates individually the TPM and nicotine outputs for selected machines as sampled at the cannula exits. There is considerable variation in the individual outputs, but the values are still more con- sistent than those observed on site visits I-IV. Table VI compares the average cannula exit values with the average input values (from Table IV) for each of the two variants. About 50-60% of the smoke particulates generated by the exposure devices are available for inhalation at the cannula exit. The Teflon smoke delivery tubes of the ADL-I's were coated with more condensed smoke than was the case for the previous visit (site visit V), which probably contributed to the lowered particulate delivery to the cannula exit. As discussed in previous Topical Reports (#32 and #38), this depletion of particulates t1irough internal deposition probably results in the animals being'offered a smoke which is relatively enriched in gas phase constituents compared to the amount of particulate phase present.

At the cannula exits, the relative ratio of the nicotine contents of the smoke of the two variants drops to about 2.1 (from 2.6 at the input to the exposure device). The data suggest that a lower efficiency for the delivery of the smoke of the HN variant is the probable cause. Ultimately, the most important chemical parameter of the inhalation exposure is the dose which the animals receive. Our best estimate of this is the amount of smoke which the animals are offered, as measured at the cannula exit. Table VII lists our estimates of the smoke dose per animal on a weekly basis for the two variants. The dose is only slightly lower than that measured on the previous visit. In terms of comparison with other NCI sponsored inhalation bioassays, the smoke dose, as measured by the amount of particulates available for inhalation, is very similar in magnitude. In this experiment, the two animal groups are being offered two distinctly different amounts of nicotine, but identical amounts of total particulates. This is the targeted dose. In an effort to more exactly define the chemical composition of the smoke which the animals are offered, we have been conducting more detailed chemical characterization studies of the particulate samples acquired on-site. Table VIII compares the chemistry of smoke samples of the LN variant entering the exposure device with that of samples reaching the cannula. With the exception of o-cresol, there appears to be little change in the relative chemical composition of the particulate phase as it passes through the exposure device, in terms of the measured com- ponents. The o-cresol appears to have been selectively depleted, but similar compounds (other cresols and phenol) do not exhibit this depletion. This monitoring visit was our first opportunity to obtain samples of gas phase constituents reaching the cannula exit of exposure systems used in a chronic inhalation study. As mentioned in the preliminary ob- servations (Topical Report #39), control samples taken prior to the trip, carried to VAH, returned with the cannula exit samples and analyzed, gave identical CO and COz values as samples remaining at ORNL. Table IX tab- ulates the TPM, nicotine, CO and CQz vlalues obtained from eight cannula exit samples of NN smoke retUrned to ORNL. The data indicates that, given cigarette-to-cigarette variability, a given exposure device can be fairly consistent in its output of both gas and particulate phases. In addition,

although there were widely differing particulate phase deliveries (two- fold range) for the eight samples, the differences in the CO/CO2 outputs are much smaller. This supports the hypothesis that gas phase delivery of the exposure system will remain constant even with changes in the in- ternal deposition of the particulates, effectively °'enriching" the smoke in gas phase constituents. Table X compares the average cannula exit values of the HN variant with those obtained analytically. Code LN values are included for com- parison. Two things should be noted. First, the CO:CO2 ratio of the exposure smoke is significantly lower than that of smoke generated analytically. Since a lower CO:CO2 ratio is often indicative of a lowered effective puff volume through the cigarette, the data may suggest that there are small air leaks around the butt of the cigarette where it fits into the holder of the ADL-I. This would lower the fraction of the 35-m1 puff taken through the cigarette,and could at least partially con- tribute to a lowered amount of particulates generated by the exposure devices, and thus ultimately available at the cannula exit. Secondly, the data verifies that little gas phase (using CO and C02 as indicator compounds) is being lost in the machines. The data here indicates that an animal is offered about 16 ml of CO and 45 rnl of C02 per cigarette. Using the analytical data from Tables X and IV, one would predict a dose (given the lower amount of nicotine generated on-site) of 20 ml of CO and 45.5 ml of C02. The reduction in CO is probably a result of a lower effective puff volume through the cigarette. Thus, based on this preliminary data, at least for the HN variant, the animals are being offered nearly all the gas phase constituents generated by the machine, but only about half of the particulate phase. e

Table I Measured Puffing Parameters for ADL-I Smoking Machines in Service at VAH on May 2-3, 1977 Cigarette Puff Period Puff Duration Puff Volume Ward No. Code Machine No. (sec) (sec) (a,1) 1 NN 35 20 2.0 31.0 2 20 2.0 34.5 33 20 1.8 37.0 6 20 1.8 36.0 37 20 2.0 30.5 2 HN 19 20 1.8 35.5 7 20 2.0 36.5 3 20 1.8 37.0 15 20 1.8 36.0 14 20 2.0 37.5 3 HN 18 20 1.7 27.0 16 20 1.7 32.0 39 20 1.5 24.0 23 20 2.1 27.5 22 20 1.8 28.0 Mean Puff Volume for HN Machines 32.7 ± 4.4 4 LN 8 20 1.8 36.5 29 20 2.0 36.5 4 20 2.0 36.5 40 20 2.0 33.5 31 20 1.7 37.0 5 LN 25 20 2.0 35.0 13 20 2.0 35.5 28 20 2.0 35.5 1 20 2.0 36.0 17 20 2.0 31.0 6 LN 30 20 2.0 34.5 38 20 2.0 34.5 24 20 2.1 35.5 34 20 2.0 35.5 36 20 1.9 33.0 Mean Puff Volume for LN Machines 35.1 ± 1.6

Table II Comparison of Cigarette Static Burn Rates Exposure Conditions at VAH vs Analytical Smoking Conditions at ORNL Cigarette Burn Ratea Code Site mg/min HNb VAH 89.9 ± 5.7 HN ORNL 67.1 ± 1.1 LNc VAH 80.3 ± 3.8 LN ORNL 73.8 ± 2.8 aBurn rate given in terms of actual weight of cigarette burned. bMeasured in Wards 1, 2, and 3. cMeasured in Wards 4 and 6.

Table III Total Particulate Matter (TPM) and Nicotine Delivery of Cigarettes Smoked on Selected ADL-I Smoking Machines in Service at VAH on May 2-3, 1977 Ward No. Cigarette Code Machine No. TPM mg/cig Nicotine mg/cig Nicotine:TPM Ratio 1 HN 2 34.5 2.69 .0780 33 39.1 3.24 .0829 6 61.1 4.39 .0718 37 46.4 3.53 .0761 35 64.8 4.33 .0668 Average 49.1 ± 13.3 3.63 ± 0.73 .0751 ± .0061 2 F{N 7 67.2 4.35 .0647 3 65.9 4.61 .0700 15 63.7 4.24 .0666 14 75.2 5.06 .0673 19 55.1 3.79 .0688 Average 65.4 ± 7.2 4.41 ± 0.47 .0675 ± .0020 3 HN 16 38.3 3.46 .0903 39 34.2 3.02 .0883 23 70.2 5.14 .0732 22 38.5 3.11 .0808 18 56.0 3.79 .0677 Average 47.4 ± 15.2 3.70 ± 0.86 .0801 ± .0097 4 LN 8 49.6 1.40 .0282 29 39.6 1.36 .0343 4 44.5 1.35 .0300 40 58.9 1.33 .0226 31 52.3 1.45 .0277 Average 49.0 ± 7.4 1.38 ± 0.05 .0286 ± .0042 5 LN 25 57.4 1.98 .0345 13 48.4 1.41 .0291 28 53.0 1.58 .0298 1 59.2 1.58 .0267 17 48.6 1.38 .0284 . Average 53.3 ± 4.9 1.59 ± 0.24 .0297 ± .0029 6 LN 30 48.1 1.54 .0320 ~ 38 52.0 1.50 .0288 ~ 24 53.6 1.54 .0287 W 34 44.2 1.32 .0299 ~ 36 54.1 1.47 .0272 p Average 50.4 ± 4.2 1.47 ± 0.09 .0293 ± .0018 a

Table IV Comparison of Gigarette Deliveries: Input to ADL-I Smoking Machine at VAH (Site Visit VI) vs Analytical Smoking Machine Conditions Cigarette Code No. of Puffs TPM, mg/cig Nicotine, mg/cig Nicotine:TPM Ratio ADL-Ia HN 16.5 ± 1.0 54.0 ± 14.2 3.92 ± 0.75 .0742 ± .0082 Analyticalb HN 18.1 ± 0.8 72.3 ± 4.4 5.11 ± 0.35 .0707 ± .0027 ADL-Ia LN 16.6 ± 0.6 50.9 ± 5.6 1.49 ± 0.16 .0292 ± .0029 Analytica1b LN 17.2 ± 0.8 66.2 ± 2.7 1.66 ± 0.11 .0251 ± .0018 aValues given are overall averages for all input samples of a given code. bAverage results for 8 cigarettes per code on the Phipps and Bird smoking machine at 3 puffs per minute, 1 cigarette per pad.