Estimating the hazards of less hazardous cigarettes. II. Study of cigarette yields of nicotine, carbon monoxide, and hydrogen cyanide in relation to levels of cotinine, carboxyhemoglobin, and thiocyanate in smokers

Yields of chemical constituents such as tar, nicotine, CO, and HCN defined by smoking machines are commonly assumed to provide a reasonable indication of the relative hazard associated with smoking a given brand of cigarette. Results reported here suggest that this assumption should be carefully reexamined. A total of 240 subjects, representing a wide range of smoking and brand characteristics, were recruited for an investigation of possible relations between brand yields and exposure (levels of carboxyhemoglobin, breath CO, plasma cotinine, plasma thiocyanate, and saliva thiocyanate). Exposure was highly correlated with consumption (number of cigarettes per day), but their was no correlation between any estimate of exposure and brand yield when level of consumption was held constant. In addition, a comparison of levels of carboxyhemoglobin and plasma thiocyanate for 16 smokers of "low-hazard" and 15 smokers of "high-hazard" cigarette brands revealed little difference between the two groups, even though average cigarette yields differed as much as 2- to 3-fold. A possible explanation for the results may be that current values for average puff volume, duration, and interval differ significantly from those used in programming smoking machines, particularly in the case of brands with low nicotine delivery.     

Chemical composition, cytotoxicity and mutagenicity of smoke from US commercial and reference cigarettes smoked under two sets of machine smoking conditions

Eight blended US market cigarettes, two blended reference cigarettes, one Bright tobacco only reference cigarette and an electrically heated prototype cigarette (EHC) were smoked under US Federal Trade Commission (FTC)/International Organisation for Standardisation (ISO) conditions and under Massachusetts Department of Public Health (MDPH) conditions. Smoke was analysed for chemical composition and in vitro toxicity. Yields (quantity/cigarette) of smoke constituents were higher under MDPH conditions compared to FTC/ISO conditions (market and reference average approximately 2.5 times; EHC approximately 1.6 times). Consistent with the higher yields, in vitro toxicity per cigarette was also higher under MDPH conditions. Concentrations (quantity/mg TPM) of nearly all smoke constituents measured decreased with increasing total particulate matter (TPM) yields as regression analyses indicated. Higher TPM yields also tended to be associated with slightly less cytotoxic and mutagenic activity per milligram TPM. Blended reference cigarettes tracked market cigarettes with similar TPM yield. The Bright cigarette displayed high cytotoxicity but low mutagenicity, while in vitro activity of the EHC was remarkably low. The TPM-dependent decreases for the market range of 5-20 mg TPM/cigarette were about 20%, irrespective of whether the increased yields were due to smoking conditions or cigarette construction. At the same TPM yield, the smoke constituent concentrations and in vitro toxicity were similar for low- and high-yield cigarettes.     

Effects of cigarette rod length on puff volume and carbon monoxide delivery in cigarette smokers

As part of a continuing series of studies to investigate the variables controlling various topographical aspects of cigarette smoking, the present study examined the extent to which cigarette rod length influenced smoking. Cigarette smoking was examined under conditions in which subjects smoked cigarettes they could not see. Both puff volume and puff duration varied as a direct function of rod length, although they were not highly correlated. Peak flow rate was not affected by rod length. Other results suggest that visual stimulus control and satiation did not affect puff volume. Comparison of puffing whole cigarettes versus short cigarette rods suggests that puff volume, but not puff duration, may be decreased in response to increased pharmacological delivery as a result of particulate build-up during smoking of a whole cigarette. Carbon monoxide (CO) exposure was substantially greater after puffing full length cigarette rods than after short cigarette rods. Comparison of these human CO data with CO delivery from syringe-simulated puffing of full length and short cigarette rods indicates that knowledge of puff volume and duration during human smoking is insufficient for accurately predicting biological (CO) exposure.     

Gas/particle partitioning and yield levels of polycyclic aromatic hydrocarbons and n-alkanes in the mainstream cigarette smoke of commercial cigarette brands.

The gas/particle partitioning of polycyclic aromatic hydrocarbons (PAHs) and n-alkanes was investigated in the mainstream smoke (MSS) from 59 commercial cigarette brands classified according to the existence of filter tip, the tar yield indicated on the packet, and the cigarette length and diameter, into 15 cigarette classes: non filter (NF), high (H), medium (M), light (L), super light (SL), ultra light (UL), one-tar yield (O), 100-mm long (H-100, L-100, SL-100, UL-100, O-100), and slim (SL-SLIM, UL-SLIM, O-SLIM). The gas/particle partitioning constant, Kp, was determined and its relationship with the subcooled liquid vapour pressure pL degrees of individual compounds was investigated. A good linear relationship was obtained for both chemical classes following the equation log Kp=mr log pL degrees+br. In all cigarette classes, PAHs were found to sorb more strongly on MSS particles than n-alkanes. Carcinogenic PAHs were detectable only in the total particulate matter (TPM) of MSS and their yields increased linearly with the TPM yield. However, when normalized against TPM, the yields of carcinogenic PAHs were quite similar in all cigarette classes with a slight drop from low tar- to high tar-yield brands suggesting probably lower biological activity per mg TPM for the latter. The nicotine-normalized PAH yields were also similar among the different cigarette classes suggesting that, if smokers adjust their smoking behavior to achieve a consistent nicotine intake, they will be exposed to an equivalent amount of carcinogenic PAHs regardless of whether they smoke full-flavored, light, or ultralight varieties.     

Determinants of puff duration in cigarette smokers: II

Studies were conducted to provide information about variables that might account for decreases in puff duration that consistently occur as a whole cigarette is smoked. In two experiments, cigarette smoking was investigated under conditions in which subjects smoked cigarettes which they could not see. Puff duration was shown to covary with manipulations of resistance to draw--increasing tobacco rod length or adding filters proximal or distal to the smoke stream increased puff duration. Filtration of the smoke stream did not influence puff duration when resistance to draw was controlled. Comparison of changes in smoke temperature with changes in puff duration across a whole cigarette, and manipulation of smoke temperature by use of different length cigarette holders suggested that temperature did not appreciably control puff duration. A final experiment with nonhuman stimulated puffing of constant puff volume showed that both tobacco rod length and cigarette brand affected puff duration and suggests the possibility that the physics of smoke passing through the cigarette may be fundamental determinant of changes in puff duration during human smoking.     

Carbon monoxide yields of cigarettes and their relation to nicotine yield and type of filter.

Carbon monoxide (CO) yields of 11 popular brands of British cigarette, two types of cigarette containing tobacco-substitute, and one brand of cigar were measured under standardized conditions. Yields of the conventional cigarettes ranged from 5.0 to 20.2 mg per cigarette (1.3 to 4.7% by volume). The cigar yielded 81.7 mg (10.0%) CO and the two semi-synthetic cigarettes 17.2 (4.2%) and 28.2 mg (6.2%) CO. Puff-by-puff analysis showed an increase in CO concentration as a cigarette is smoked. In brands with nicotine yields over 1.0 mg no relationship was apparent between nicotine yield and CO yield, and the filters of cigarettes in this category did not appear to reduce the CO yield. In the low nicotine cigarettes with ventilated filters there appeared to be some correlation between nicotine yield and CO yield, and these filters were highly effective in reducing CO yield, owing mainly to the ventilation. We suggest that official publication of CO yields might motivate manufacturers to produce cigarettes with lower yields.     

Effect of filter vent blocking on carbon monoxide exposure from selected lower tar cigarette brands.

Two studies were conducted to determine the effect of blocking filter vents on carbon monoxide (CO) exposure under ad lib smoking conditions. In Study 1, 12 daily cigarette smokers smoked cigarettes from the brands Now (1 mg tar by the FTC Method) and Marlboro Lights (10 mg tar) under each of two vent-blocking conditions (unblocked and finger blocked). Blocking filter vents with fingers led to an 85% increase in CO for the brand Now, but had no added effect on CO exposure from the Marlboro Lights. In Study 2, another 12 daily cigarette smokers smoked cigarettes from each of four additional brands: Carlton (1 mg tar), Now (2 mg tar), Virginia Slims Ultra-lights (5 mg tar), and Virginia Slims Lights (8 mg tar). Blocking filter vents with the lips caused all four brands to produce equal CO exposures. Blocking vents increased smokers' exposure to CO by 239% when smoking Carltons and by 44% when smoking Nows. No significant increases in CO with blocking were found for either of the Virginia Slims brands. These results suggest that the degree to which a brand is ventilated determines whether that brand is susceptible to increased CO yields as a result of vent blocking.     

Investigation of mainstream smoke aerosol of the argileh water pipe.

A first-generation smoking machine and protocol have been developed in order to study the mainstream smoke aerosol and elucidate thermal-fluid processes of the argileh water pipe. Results using a common mo'assel tobacco mixture show that, contrary to popular perceptions, the mainstream smoke contains significant amounts of nicotine, "tar" and heavy metals. With a standard smoking protocol of 100 puffs of 3 s duration spaced at 30-s intervals, the following results were obtained in a single smoking session: 2.25 mg nicotine, 242 mg nicotine-free dry particulate matter (NFDPM), and relative to the smoke of a single cigarette, high levels of arsenic, chromium and lead. It was found that increasing puff frequency increased the NFDPM but had little effect on nicotine delivery, while removing the water from the bowl increased by several-fold the nicotine, but had little effect on NFDPM. It was also found that the charcoal disk heat source contributed less than 2% of total particulate matter (TPM), and that characteristic temperatures of the tobacco varied from 450 degrees C nearest the heat source to 50 degrees C furthest away, indicating that the NFDPM is likely a result of devolatilization rather than chemical reaction, and will thus differ significantly in composition from that of cigarette smoke.     

Effects of smoking abstinence and chain-smoking on puffing topography and diurnal nicotine exposure.

Effects of chain-smoking, a 15-h smoking abstinence, and the nicotine yield of cigarettes on puff indices were studied in eight healthy smokers by using a controlled crossover study design. Puff parameters were measured puff by puff with a portable measuring device when 10 or 20 cigarettes, with nicotine yields of 0.3 and 1.0 mg, were smoked per day. The interval between sessions was 1 h, and the 20 cigarettes per day were chain-smoked 2 at a time. Serum cotinine indicated that smokers compensate completely for the lower nicotine delivery from the 0.3-mg cigarette. Smokers almost doubled total puff volume per cigarette and per day mainly by taking more puffs from the low-nicotine cigarettes and slightly prolonging puff duration. However, nicotine deprivation and chain-smoking had a relatively minor effect on puffing indices with both brands, a fact that agrees poorly with the nicotine titration hypothesis. However, in the course of every single cigarette of the day smokers significantly reduced puff duration and puff volume toward the end of the cigarette, which probably involves satiation of the nicotine crave but may also be due to changes in taste of the smoke.     

Evaluation of the potential effects of ingredients added to cigarettes. Part 2: chemical composition of mainstream smoke.

Cigarette mainstream smoke from blended research cigarettes with and without the addition of ingredients was analyzed for its chemical composition. In total, 333 ingredients commonly used in cigarette manufacturing were assigned to three different groups. Each group of ingredients was introduced at a low and a high level to the test cigarettes. The list of the 51 smoke constituents determined is based on those analytes suggested for analysis in a US Consumer Product Safety Commission proposal for low ignition cigarettes and cigarette smoke constituents identified by the International Agency for Research on Cancer as worthy of concern and characterized as carcinogens. An increase in the yield of total particulate matter (TPM) in the range of 13 to 28% relative to the control cigarette without ingredients was observed for all test cigarettes. This was presumably caused by the higher transfer rates of the added ingredients to the smoke compared to the transfer from the tobacco part of the filler. When the yields of individual constituents were normalized to the TPM yields, a reduction in the majority of the constituents was observed when compared to the control. For one of the ingredient groups this reduction was especially high: for phenols a maximum of 70%, for polycyclic aromatic hydrocarbons 50%, and for N-nitrosamines 45%. An increase in the amount relative to TPM was observed for a few smoke constituents: hydrogen cyanide and cadmium (one ingredient group), formaldehyde (one ingredient group), and resorcinol and lead (two ingredient groups). These results are consistent with the lack of any increased activity in the in vitro and in vivo assays in this same series of studies (Food and Chemical Toxicology 2002, 40, 105-111; Food and Chemical Toxicology 2002, 40, 113-131). An overall assessment of our data suggests that these ingredients, when added to the tobacco, do not add to the toxicity of smoke, even at the elevated levels tested in this series of studies.     

Puffing behavior during the smoking of a single cigarette in a naturalistic environment.

The 36 participants in this study were habitual low-yield cigarette smokers, medium-yield cigarette smokers, and switchers from medium- to low-yield cigarettes. All participants smoked both low- (0.4 mg) and medium-nicotine (0.9 mg) cigarettes during the study. Puffing indices were recorded during the first two cigarettes, after an overnight abstinence of smoking, by a portable flowmeter processor unit in a naturalistic environment. The puff volumes per cigarette and per day were significantly lower while switching to higher-yield cigarettes, mainly due to a decrease in the number of puffs and longer interpuff intervals, but also due to a decline in puff duration and flow rate. However, the downregulation by puff volume was incomplete, at most two thirds, as calculated by machine smoking yields. Within the course of smoking a single cigarette, the flow rate was quite stable, puff duration and puff volume decreased toward the end of the cigarette, and interpuff interval was longest during the middle of the cigarette. Total puff volumes per cigarette were similar in the first two cigarettes of the day after an overnight abstinence of smoking, with no significant differences in other puff parameters. Diurnal cotinine excretion revealed that nicotine titration in switching situations was very accurate among switchers and medium-yield cigarette smokers, but not among the low-yield cigarette smokers, and so called oversmoking was found with the higher-nicotine brand. Preferred cigarette type had little effect on the puffing patterns of smokers in single cigarettes.     

Estimating the hazards of "less hazardous" cigarettes. I. Tar, nicotine, carbon monoxide, acrolein, hydrogen cyanide, and total aldehyde deliveries of Canadian cigarettes

The tar, nicotine, CO, HCN, total aldehyde, and acrolein deliveries of 102 brands of Canadian cigarettes have been determined. On the basis of these deliveries, 15 brands (9% of sales) were categorized as low hazard and 9 brands (10% of sales) as high hazards. All six constituents were used for the classification since for most brands tar was a poor indicator of gas-phase deliveries. As a result, smokers who indiscriminately switch to a brand with a lower tar delivery may inadvertently increase their exposure to gas-phase constituents such as CO and increase their risk of smoking-related pathology. With respect to Canadian cigarettes, the choice of a 30-mm standard butt length may result in omission of some of the available tobacco from the testing procedure, thus reducing the value of tar level as a guide to choosing a less harmful cigarette.     

Free-base nicotine in tobacco products. Part I. Determination of free-base nicotine in the particulate phase of mainstream cigarette smoke and the relevance of these findings to product design parameters

The free-base nicotine (FBN) content of mainstream cigarette smoke (MSS) has been discussed in the peer-reviewed literature and popular press. It has been alleged that manufacturers adjust product design features to increase the percentage of total nicotine (TN) in the MSS gas–vapor phase that is unprotonated [P_g,nic(%)] and/or the fraction of nicotine in the MSS total particulate matter (TPM) that is unprotonated (FBN/TN). Our research showed the Health Canada Intensive smoking conditions negated the effects of blend and cigarette design features reported to raise the pH of TPM collected under ISO or US FTC conditions. Our research also showed that when additive-free Canadian cigarettes were smoked under ISO conditions, the FBN/TN ratio increased as the tar/nicotine ratio decreased. Our findings are in line with other studies that have questioned allegations of a relationship between use of ammonia and its compounds as tobacco additives and amounts of unprotonated nicotine in MSS. In addition, the experimental work demonstrated how use of solid-phase microextraction to estimate FBN can yield erroneously high results due to improper conditioning and/or smoking of the cigarettes. Our research showed that there is no longer any scientific support for regulators to require smoke pH and FBN determinations on cigarette products.     

Toxicological evaluation of potassium sorbate added to cigarette tobacco.

Potassium sorbate (PS) may be incorporated in blended cigarette tobacco either as a mold growth inhibitor in processed tobacco sheet material, or as a preservative in flavor systems or paper adhesives. To evaluate the effect of PS addition, neat material pyrolysis studies, smoke chemistry and biological activity studies (bacterial mutagenicity, cytotoxicity, in vivo micronucleus, and 90-day nose-only rat inhalation) with mainstream smoke, or mainstream smoke preparations from cigarettes containing various measured levels of PS (0%, 0.15%, 1.6%, and 3.7%) were performed. At simulated tobacco burning temperatures up to 1000 degrees C, neat PS completely pyrolyzed to form aromatic ring materials including benzene, toluene, substituted benzenes, naphthalene, and substituted naphthalenes. Under machine smoking conditions (FTC/ISO), high levels of PS may alter the burning characteristics of the cigarette leading to decreased puff count, total particulate matter, carbon monoxide, hydrogen cyanide, 2-nitropropane, and tobacco specific nitrosamines yields in the smoke, while increasing the yield of nicotine, 1,3-butadiene, isoprene, and some PAHs. Biological studies indicated no relevant differences in the genotoxic or cytotoxic potential of either mainstream smoke from cigarettes with or without added PS. Rats exposed to mainstream cigarette smoke developed respiratory tract changes consistent with those seen in previous smoke inhalation studies, with no relevant histopathological differences between the control and the PS test cigarette groups. These studies demonstrated that high levels of PS could alter the burning rate of the tobacco leading to alteration in the smoke chemistry profile. Yet, based on the panel of biological endpoints monitored here, it appeared that added PS produced little relevant change in the overall toxicity profile of smoke.     

Deposition and distribution of the total particulate matter of cigarette smoke in mice using a large-capacity smoke exposure system

A newly developed automatic smoke exposure machine (SEM II) was used to generate [¹⁴C]dotriacontane-labeled University of Kentucky reference 2A1 or 2R1 cigarette smoke. The SEM II is a large-capacity (480 mice) dynamic smoke exposure system in which smoke is routed through the animal containment system as a continuously flowing stream. Mice are restrained about the neck in stock-like holders for “nose-only” exposure. Using standard smoke exposure conditions, the deposition and internal distribution of the total particulate matter (TPM) from cigarette smoke was determined in BC3Fl/Cum male and female mice. Results show: (a) smoke exposure conditions can be varied so that deposition from 30 to 200 μg TPM/lung can be obtained, (b) 80–90% of the TPM deposition was found in the respiratory tissues, (c) the mouse-to-mouse variation for TPM deposition in pulmonary tissue was ～20%, (d) similar deposition and distribution of TPM was observed in male and female mice, and (e) deposition and distribution of TPM was not altered in mice exposed to smoke on a daily basis over a 6-month period of time.     

Evaluation of functional relationships for predicting mainstream smoke constituent machine yields for conventional cigarettes from the Japanese market

The objective of this study was to predict mainstream smoke constituent yields for conventional filter cigarette brands on sale in Japan between 2004 and 2005. Mainstream smoke was generated under ISO machine smoking conditions. Developed functional relationships indicate the validity of benchmarking even for a market which is characterized by a diversity of tobacco blend types. Smoke yields were in general well predicted by linear regression with "tar" (R2>or=0.7). Blend-type-sensitive analytes like tobacco-specific nitrosamines showed improved prediction relationships after blend stratification or regressing against nitric oxide (NO, R(2)>0.7). Relationships calculated from 83 exploratory brands were validated with a subset of 23 validation brands. Seventy-five to one-hundred percent of the validation brand yields were inside the 95% prediction intervals. The mean-relative prediction error over all analytes was 24% after stratification. Smoke constituents yields analyzed in 2002 from 96 Japanese market products were well predicted and indicate the model validity over time. Similar relationships were observed when comparing American blended filter cigarette yields from Japan and worldwide markets. Consistent with reported results from previous benchmark studies and market surveys mainstream smoke constituent yields are well predictable when "tar" (and NO) yields are known.     

Determinants of puff duration in cigarette smokers: I

This research was undertaken to provide information about variables that might account for the decreases in puff duration that consistently occur as a whole cigarette is smoked. Cigarette smoking was investigated under conditions in which subjects smoked cigarettes which they could not see. In a series of three experiments, the length of the tobacco rod, the length of the cigarette holder, and the cigarette nicotine delivery were systematically manipulated. The results showed that puff duration correlates with the length of the tobacco rod, and that visual stimulus control, satiation, distance from the burning ember to the smoker's mouth, nicotine delivery, particulate build-up during smoking, and subjective acceptability of cigarette smoke do not contribute significantly to the control of puff duration.     

Sex differences in the subjective and reinforcing effects of cigarette nicotine dose

RATIONALE: Some research with novel nicotine delivery methods suggests that nicotine itself may be less reinforcing in women than in men. However, sex differences in the reinforcing effects of nicotine dose via cigarette smoking have received little attention. OBJECTIVES: Sex differences in the subjective and reinforcing effects of smoking were examined as a function of two cigarette nicotine "dose" levels (moderate - subjects' preferred brand, > or = 0.7 mg yield; low - Carlton "ultra-light", 0.1 mg yield). METHODS: Male and female smokers ( n = 30) participated in three sessions, the first two involving independent assessment (only one brand available), and the third involving concurrent assessment (both brands available), of subjective ratings (e.g. "liking") and reinforcement for the two cigarette brands. Subjects were blind to the brand of each cigarette, and subjects abstained overnight prior to each session. Reinforcement was determined by responses on a computer task to earn single puffs on the designated cigarette. RESULTS: Subjective ratings differed between the low versus moderate cigarette nicotine dose under both independent and concurrent assessment conditions, as expected. Notably, this dose difference was smaller in women than in men (i.e. significant sex by dose interactions). The dose effect on smoke reinforcement also was smaller in women than men, but only under the independent and not concurrent assessment condition. CONCLUSIONS: These results indicate that cigarette nicotine dose is a less important influence on the subjective and, under some conditions, reinforcing effects of smoking in women than in men.     

Behavioral and biochemical effects of gradual reductions in cigarette yields in pregnant and nonpregnant smokers

Smoking-related risks have been well-documented for both the smoker and the pregnant smoker's unborn child, but the risks associated with low tar/nicotine cigarette smoking are still controversial. The present study examined some of the behavioral and biochemical effects of gradual reductions in tar and nicotine yields in six pregnant and six nonpregnant smokers. Over four sessions spanning a 6-week period, smokers switched to cigarette brands progressively lower in tar and nicotine. Examination of the topographical variables assessed both during (cigarette frequency, puff frequency, and cigarette duration) and between sessions (daily cigarette rate and nicotine intake) revealed significant decreases in both pregnant and nonpregnant smokers' cigarette duration and nicotine intake. Also observed were significantly lower and less variable carboxyhemoglobin (COHb) levels among the pregnant smokers when they smoked the lowest tar and nicotine brands. However, even the pregnant smokers' lower mean COHb levels did not drop below the 3% minimal cardiovascular risk level. The pregnant smokers also tended to have lower and less variable salivary thiocyanate (SCN) levels, but these differences were nonsignificant. The results were discussed in terms of implications for controlled smoking treatment programs for pregnant smokers.     

Pharmacologic and sensorimotor components of satiation in cigarette smoking

To examine mechanisms underlying satiation in cigarette smoking, 18 smokers received intravenous (i.v.) nicotine, alone or in combination with denicotinized cigarette smoke. Nicotine was administered using programmed presentations of either pulsed injections or continuous infusions, with i.v. saline serving as a control. A high-nicotine cigarette smoke condition (usual brand) was also presented. During each of the six test sessions, subjects were allowed to puff on their usual brands of cigarette ad libitum while the programmed satiation conditions were in force. Administration of i.v. nicotine caused a small suppression of ad libitum smoking behavior; denicotinized smoke produced a significantly larger reduction, showing that short-term satiation is more dependent on the presentation of smoke than delivery of nicotine per se. However, denicotinized smoke alone did not have as much effect as puffs from the usual brands of cigarettes. The combination of i.v. nicotine and denicotinized smoke puffs produced equivalent satiation to that of the usual brand. Cigarette craving and negative affect were partially relieved by iv nicotine presentations as well as by denicotinized smoke, and again the combination of i.v. nicotine and denicotinized smoke approximated the effects of the usual brand. The results of this study underscore the importance of both sensorimotor aspects of smoking and the pharmacologic effects of nicotine in tobacco dependence.