Cigarette smoking as a risk for cardiovascular disease III: Biochemical effects with higher nicotine yield cigarettes

Subjects who smoked a medium range nicotine yield cigarette were given a higher nicotine yield cigarette (an increase of 0.34 mg nicotine) to smoke ad libitum for two weeks. Plasma nicotine, cotinine, thiocyanate and blood carboxyhemoglobin levels were determined as well as various physiological parameters including heart rate and blood pressure. Increases in plasma nicotine were most directly correlated to heart rate when smokers were first challenged with a higher nicotine yield cigarette (r = 0.85); less directly correlated after a two-week acclimatization period (r = 0.42) and poorly related to their customary product (r = 0.23). Interestingly, it was noted that subjects did not compensate for higher nicotine yield by smoking fewer cigarettes per day when incremental nicotine changes were realistic. They did, however, show higher plasma nicotine, thiocyanate and an upward trend in plasma cotinine with the stronger cigarettes. These increases in cigarette constituents present in plasma, coupled with increasing correlation of heart rate and nicotine uptake, lead us to suggest that uptitration of smokers might cause them to establish new baseline levels. These findings have important health implications in light of recent suggestions to increase the nicotine yet decrease the tar of cigarettes in an attempt to overcome smoker compensation phenomena observed with low yield products.     

Cigarette smoking as a risk for cardiovascular disease V: Biochemical parameters with increased and decreased nicotine content cigarettes

Cigarette smokers were assessed for customary smoking behavior and then were assigned a cigarette which was 0.4 mg higher or lower in nicotine and after 4 weeks, were returned to their customary brand. Biochemical indices of smoking behavior including blood carboxyhemoglobin (COHb), plasma nicotine, cotinine and thiocyanate (-SCN) were measured every 2 weeks. When nicotine availability was increased, smokers received an increased nicotine bolus per puff as determined by plasma nicotine and did not alter smoking topography or cigarettes per day. Over the 4 weeks, plasma cotinine increased without corresponding increases in COHb and -SCN. The return to standard brand resulted in declining cotinine levels but increasing COHb and -SCN, suggesting altered inhalation patterns. In smokers switched to a low yield cigarette, there was a decrease in the nicotine obtained per cigarette followed by a steady rise in plasma cotinine, -SCN and blood COHb over the 4-week period. A positive correlation was observed between cotinine and the gas phase constituents during the change to lower yield and back to standard brand cigarettes. These results indicate that cigarette smokers compensate for decreased nicotine yield with concomitant increases in gas phase components. In addition, increased nicotine availability results in an increased body burden of nicotine and “tar,” but not gas phase constituents. The relative risks of cardiovascular disease under these two situations, which increase exposure to nicotine or gas phase components, deserve careful consideration.     

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.     

Cigarette smoke inhalation and blood dose markers in beagle dogs

The time course of three tobacco-related blood dose markers was determined in beagle dogs during and after two-, four-, and six-cigarette acute smoke exposures. Venous blood samples were taken from a jugular catheter at selected intervals and analyzed for nicotine, cotinine, and carboxyhemoglobin (COHb). Smoke was generated from reference cigarettes (1.91 mg of nicotine) by a machine and delivered to the trachea of tracheostomized dogs. Cigarettes were chain-smoked in pairs with a 5-min break between pairs when four or six cigarettes were smoked. Blood nicotine, cotinine, and COHb levels all rose during smoke inhalation. Peak values of COHb were dosimetrically related to the number of cigarettes, while peak nicotine and cotinine values were not related consistently. The exposure protocol used in this study produced blood levels of all three measured parameters which were in the range of published values for human smokers, so that it is possible to approximate acute human cigarette smoke inhalation in the beagle dog model.     

Analytical cigarette yields as predictors of smoke bioavailability

The smoke intake of 865 undisturbed smokers of over 10 cigarettes per day was measured using plasma nicotine and cotinine, and expired carbon monoxide (CO) as markers. While nicotine yields, according to Federal Trade Commission (FTC) analytical standards, varied 16-fold from 0.1 to 1.6 mg/cigarette, the corresponding plasma nicotine values varied from around 25 to 45 ng/ml, and estimated mean nicotine intake of smokers varied from around 0.75 to 1.25 mg/cigarette. Expired CO and plasma cotinine values also varied in similar proportion, but mean daily cigarette consumption was independent of the FTC nicotine yield of the cigarettes smoked. The results indicate that pharmacodynamic satiation causes behavioral regulation, and that smokers of very high yield brands compensate downward, and vice versa. The ratio of tar yield to nicotine yield usually increases with increasing tar yield; therefore tar intake is likely to increase at higher tar yields, even though the increment of nicotine intake is small. It follows that FTC analytical determinations are poor predictors of relative intake of nicotine, CO, or tar, while rankings based on mean tar-to-nicotine ratio of a brand's smoke could be more meaningful. Moreover, the considerable variation of individual smoking behavior suggests that precise numerical rankings of cigarettes are not justified. An analogic ranking of cigarettes into a few broad classes would better reflect the realities and expectations of average consumers.     

Passive and active exposure to cigarette smoke in a smoking experiment

Six volunteer female habitual smokers were exposed during a 2-wk experimental period to cigarette smoke, both actively and passively, in an exposure chamber (volume 10 m3, average air exchange rate 6.8 times/h), where the ambient carbon monoxide, particle, and aldehyde concentrations were monitored. Three of the six subjects were smoking at the time, 2 cigarettes (filtered, self-burning low tar brand) per person per hour, 30 cigarettes altogether during each of the 5-h experimental days in the chamber. Samples of blood and urine were taken from each subject after 3 nonsmoking days and after each day of active or passive smoking. Among the parameters tested, blood carboxyhemoglobin, plasma cotinine, and urinary mutagenicity were higher in samples taken after active smoking than after nonsmoking periods. Although the exposure conditions were similar for all subjects, the parameters measured showed quite high interindividual variation. Thioethers and thiocyanates were not significantly elevated in the active smoking samples; neither were there any differences during this short experimental period in the sister chromatid exchange frequencies. The only parameters showing an increasing trend after passive exposure, as compared with nonsmoking samples, were urinary mutagenicity and plasma cotinine, the main metabolite of nicotine.     

Plasma nicotine and cotinine in tobacco smoke exposed beagle dogs

Nicotine and cotinine have been determined in plasma samples from 87 beagle dogs chronically exposed to cigarette smoke with three different levels of nicotine. An additional 18 sham-exposed animals were included in the study as controls. Smoke was administered to the animals through permanent tracheostomas via cuffed tracheostomy tubes and was generated from reference cigarettes under standard puffing parameters by ADL-II smoking machines. The dogs were exposed for an average of 2 years prior to sample collection. The results from blood samples collected at specific intervals in the daily exposure schedules indicate that nicotine may be useful as a relative index of smoke exposure. At elevated exposure levels, average blood concentrations were related to the number of cigarettes smoked as well as the nitocine delivery of the cigarette. Cotinine was found to increase more slowly than nicotine and was also metabolized more rapidly than in humans. Overall, the study affords an examination of the relationship of plasma nicotine and cotinine with estimated nicotine exposure.     

Effects of cigarette nicotine content on smoking behavior of baboons

Human cigarette smokers modify the way in which they smoke cigarettes of differing nicotine content, apparently to maintain nicotine exposure at a preferred level. The effects of changing from moderate to high or low nicotine content cigarettes were examined in 11 baboons (superspecies Papio cynocephalus) trained to smoke cigarettes for water rewards. Relative to the moderate nicotine content cigarette, the animals took significantly (p < .05) more puffs on the high nicotine content cigarette, and the puffs on the high nicotine cigarette were significantly larger in volume. The animals made the same number of puffs, relative to the moderate nicotine content cigarette, on the low nicotine content cigarette, but the volume of the puffs was significantly smaller. The cotinine output in urine varied significantly and was directly related to cigarette nicotine content; cotinine is the primary metabolite of nicotine. Baboons, like people, prefer high nicotine content cigarettes. Nonhuman primates also regulate nicotine exposure by modification of their puffing behavior. These results indicate that the nonhuman primate also can be used as a model for the investigation of the behavioral aspects of cigarette smoking.     

Puffing topography as a determinant of smoke exposure

Puffing topography variables were measured in a well-characterized, male population smoking their own brand of cigarette. Of the puffing topography variables, interpuff interval appeared to be the primary determinant of blood concentrations of smoke constituents: however, preliminary data in a homogeneous population according to the nicotine yield of their cigarette suggest that total puff volume per cigarette may also be a significant determinant of blood levels of smoke constituents. Smokers of low nicotine yield cigarettes partially compensated for these lower yields by increasing the total volume puffed per cigarette. Observed differences in puffing topography associated with increased daily cigarette consumption and cumulative smoking history were consistent with a higher smoke exposure per cigarette. Further, although both alcohol and coffee consumption are associated with present and cumulative smoking history, coffee consumption is uniquely associated with differences in puffing topography consistent with a higher smoke exposure per cigarette. However, by multiple regression analyses, neither coffee nor alcohol consumption histories added significantly to the prediction of blood concentrations of smoke constituents over that obtained by smoking history and puffing topography.     

Effects of a nicotine-enriched cigarette on nicotine titration,daily cigarette consumption,and levels of carbon monoxide,cotinine, and nicotine

To test whether cigarettes with low tar, low carbon monoxide, and medium nicotine yield produce less dangerous effects than cigarettes low in tar and CO but high in nicotine, 12 subjects were recruited to smoke nicotine-enriched cigarettes. The subjects smoked three types of cigarettes in the three experimental conditions: (1) their own brand; (2) cigarettes with 4.8 mg tar, 4.0mg CO, and 0.5 mg nicotine; (3) cigarettes with 5.8 mg tar, 4.1 mg CO, and 1.1 mg nicotine. Subjects monitored their daily consumption for 12 weeks; 4 weeks for each condition. During laboratory visits, the subjects smoked a cigarette while their heart rate and carbon monoxide in expired air were measured pre- and post-smoking. A blood sample was drawn and analyzed for nicotine and cotinine in each experimental condition. No significant differences in daily cigarette consumption were found, although a trend (P<0.07) in the direction of fewer nicotine-enriched cigarettes per day was found. Levels of CO varied significantly among the three conditions: The subjects' own brands yielded the highest level, while the nicotine-enriched cigarette yielded the lowest level. No differences were found for nicotine or cotinine levels. A second purpose of the experiment was to record the degree of nicotine titration displayed by individual smokers, tar and CO levels remained constant in the experimental cigarettes. No general titration effect was observed, although for daily consumption it approached significance. When the subjects' nicotine dependence, measured with a tolerance questionnaire, was taken into acount, a correlation with daily consumption was found (r=77, P<0.005). A cigarette with low tar and CO, but medium to high nicotine yield, would seem to produce less hazardous effects and is worthy of further investigation. The controversial question of whether smokers titrate for nicotine is a function of the individual's nicotine dependence.     

Ultralow-yield cigarettes and type of ventilation: The role of ventilation blocking

Habitual smokers of perforation-ventilated cigarettes and of channel-ventilated cigarettes (18 male and 18 female subjects each; nicotine yield 0.1–0.3 mg, 0.2 mg, respectively) were compared with respect to different smoke exposure indicators and puffing behavior. The role of ventilation blocking was assessed by comparing normal lip contact smoking with smoking through a cigarette holder. The presmoking concentrations (plasma nicotine, cotinine, respiratory CO) were higher for channel-filter than for perforation-ventilated cigarettes, as were the pre- to postsmoking boosts (nicotine, CO) with normal lip smoking. Holder smoking resulted in lower boosts than lip smoking for the channel filter cigarettes, although the puffing behavior was considerably intensified. The boosts for perforation-ventilated cigarettes remained unchanged and were reached with only moderately intensified puffing behavior. The results indicate the importance of ventilation blocking in everyday lip smoking for channel-filter cigarettes, but not for conventional, perforated cigarettes.     

Relationship between machine-derived smoke yields and biomarkers in cigarette smokers in Germany

In order to determine whether smokers of cigarettes in the contemporary yield ranges of the German market (0.1-1.0mg nicotine, 1-10mg tar) differ in their actual exposure to various smoke constituents, we performed a field study with 274 smokers and 100 non-smokers. The following biomarkers were determined: In 24-h urine: Nicotine equivalents (molar sum of nicotine, cotinine, trans-3'-hydroxycotinine and their respective glucuronides), 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL, metabolite of the tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone, NNK), 3-hydroxypropylmercapturic acid (metabolite of acrolein), trans,trans-muconic acid, S-phenylmercapturic acid (metabolites of benzene), 1-hydroxypyrene (metabolite of pyrene); in saliva: Cotinine and trans-3'-hydroxycotinine; in exhaled air: Carbon monoxide; in blood: Methyl-, hydroxyethyl-, cyanoethyl- (biomarker of acrylonitrile) and carbamoylethylvaline (biomarker of acrylamide) hemoglobin adducts. All biomarkers were found to be significantly higher in smokers compared to non-smokers and showed strong correlations with the daily cigarette consumption. Biomarker levels and per cigarette increases in smokers were at most weakly related to the machine-derived smoke yields. It is concluded that machine-derived yields of cigarettes from the contemporary German cigarette market have little or no impact on the actual smoking-related exposure determined by suitable biomarkers.     

Levels of cigarette availability and exposure in black and white women and efficient smokers

Purposes of this investigation were to examine differences in smoke exposure and smoking topography across three smoking conditions: usual number of cigarettes, restricted (50%) and increased (167%) simulating restricted and unrestricted cigarette availability. A repeated-measures counterbalanced design with a sample of 25 women (13 African Americans; 12 Caucasians) was implemented with a 6-day inpatient protocol conducted in the General Clinical Research Center (GCRC). There were significantly larger percentage increases in carbon monoxide (CO) postcigarette in the restricted condition compared to usual and increased condition. Women with baseline cotinine/cigarette ratios >20 ng/ml/cigarette, considered efficient smokers, had significantly higher CO increases postcigarette at baseline than participants with lower cotinine/cigarette ratios, yet increased this exposure further during the restricted condition. Efficient smokers had significantly higher nicotine boost in the restricted condition compared to less efficient smokers. Differences by ethnicity were also noted with significantly higher CO percentage increases pre- to postcigarette in African Americans across all conditions, compared to Caucasians. Levels of smoke exposure postcigarette in persons who reduce cigarettes per day in response to restricted cigarette availability may be substantial.     

The effects of a restricted feeding regimen on cigarette smoking in humans.

The effects of 3 days of restricted feeding (800 kcal/day) on cigarette consumption, smoke exposure, and mood were studied in five male research volunteers. A within-subjects design was used in which subjects were exposed in an inpatient research unit to either a nutritionally-balanced diet containing 800 kcal (RESTRICTED DIET) or 3,000 kcal (NORMAL DIET) per day for 3 consecutive days. At least 2 weeks separated diet conditions. Dependent measures included number of cigarettes smoked per day in each diet condition, biological exposure levels (carbon monoxide and plasma cotinine levels), and mood. Number of cigarettes smoked per day did not differ significantly across diet conditions. Biological exposure to carbon monoxide and to cotinine, a metabolite of nicotine indicative of chronic nicotine exposure, also did not differ significantly between conditions. Fatigue scores from the Profile of Mood States were significantly elevated in the RESTRICTED DIET condition. Not surprisingly, subjects in this condition also reported feeling more hungry throughout the day than in the NORMAL DIET condition. From our study results, we conclude that a short period of "dieting," and the resulting hunger elicited from such a diet, do not increase cigarette consumption or smoke exposure in humans.     

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.     

Hydroxyethylvaline adduct formation in haemoglobin as a biological monitor of cigarette smoke intake

The ethylene oxide adduct formed on the N-terminal valine in haemoglobin was investigated as a biological monitor of tobacco smoke intake. The modified method developed for the determination of the hydroxyethylvaline adduct (HOEtVal) involved reaction of globin with pentafluorophenyl isothiocyanate, extraction of the HOEtVal thiohydantoin product, derivatization of this by trimethylsilylation and quantitation by capillary gas chromatography with selective ion monitoring mass spectrometry using a tetradeuterated internal standard. The method was applied to globin samples from 26 habitual cigarette smokers and 24 non-smokers. There was a significant correlation between cigarette smoke intake as measured by the average number of cigarettes smoked per day and HOEtVal levels (r=0.537, p<0.01). Background levels were found in non-smokers (mean 49.9 pmol/g Hb, range 22–106 pmol/g Hb). Smoking increased these levels by 71 pmol/g Hb/ 10 cigarettes per day.Cotinine levels in plasma of the smokers were determined by GC-NPD using 2-methyl-4-nitroaniline as internal standard. For non-smokers cotinine was determined by GC-MS selective ion monitoring using d₃-methylcotinine as internal standard. There was no correlation between number of cigarettes smoked per day and cotinine levels (r=0.297, p>0.05) although cotinine was correlated with HOEtVal (r=0.43, p<0.01).The HOEtVal adduct levels thus appear to be a suitable biomonitor for exposure to hydroxyethylating agents in cigarette smoke, reflecting an integrated dose over the erythrocyte lifetime. This is in contrast to plasma cotinine determinations which reflect only the previous day's exposure to nicotine in smoke.     

In utero exposure to 1R4F reference cigarette smoke: evaluation of developmental toxicity.

The potential developmental effects of 1R4F reference cigarette smoke were examined using Sprague-Dawley rats exposed for 2 h/day, 7 days/week, by nose-only inhalation at target mainstream smoke concentrations of 150, 300, and 600 mg/m3 total particulate matter (TPM). Males were exposed 4 weeks prior to and during mating, with females exposed 2 weeks prior to mating and during mating, and through gestation day (GD) 20. Sham controls received filtered air to simulate nose-only exposure, while cage controls were maintained untreated. Smoke exposure was confirmed through biomarker evaluation (parental: carboxyhemoglobin, nicotine, and cotinine; fetal: nicotine and cotinine). Characteristic cigarette smoke-related histopathologic changes including nasal epithelial hyperplasia and squamous metaplasia and pigmented macrophages in the lung were observed in all exposed parental groups. Maternal toxicity during gestation was indicated at smoke concentrations of 300 and 600 mg TPM/m3, where corrected total body weight gain was significantly (p 相似文献   

Good relationship between saliva cotinine kinetics and plasma cotinine kinetics after smoking one cigarette

This study investigated the relationship between plasma and saliva cotinine kinetics after smoking one cigarette and the relationship between cotinine kinetics and estimated nicotine intake, which was calculated as mouth level exposure (MLE) of nicotine, from smoking two test cigarettes with different nicotine yields. This study was conducted in 16 healthy adult Japanese smokers, who did not have null nor reduced-activity alleles of CYP2A6, with a quasi-randomized crossover design of smoking a low-tar cigarette or a high-tar cigarette. Saliva cotinine showed similar concentration profiles to plasma cotinine, and all of the calculated pharmacokinetic parameters of cotinine showed the same values in plasma and saliva. The C_max and AUC of cotinine showed almost the same dose-responsiveness to the estimated MLE of nicotine between plasma and saliva, but the t_max and t_1/2 of cotinine were not affected by the estimated MLE of nicotine in either plasma or saliva. The results show that saliva cotinine kinetics reflects plasma cotinine kinetics, and measurement of saliva cotinine concentration gives the same information as plasma cotinine on the nicotine intake. Thus, saliva cotinine would be a good and less-invasive exposure marker of cigarette smoke, reflecting the plasma cotinine concentration and kinetics.     

Blood nicotine, smoke exposure and tobacco withdrawal symptoms

The relationship between tobacco withdrawal symptoms and pre- and post-cigarette blood nicotine levels, pre-cigarette cotinine levels, change in nicotine level from pre- to post-cigarette, half-life for nicotine, and total smoke exposure was examined in 20 smokers. Subjects' reports of craving for cigarettes were significantly related to blood nicotine/cotinine levels and change in nicotine level from pre- to post-cigarette; questionnaire measures of confusion and number of awakenings during sleep was related to half-life for nicotine; and number of awakenings during sleep was related to behavioral measures of total smoke exposure. These results suggests some symptoms of tobacco withdrawal are related to nicotine deprivation while others are not.     

Hair analysis--a biological marker for passive smoking in pregnancy and childhood.

Passive smoking has been shown to adversely affect the health of infants and children. We used hair analysis for nicotine and its metabolite cotinine as a biological marker for exposure to smoking in these two groups. Using radioimmunoassay we measured maternal and fetal hair concentrations of nicotine and cotinine in the mother-infant pairs belonging to three different groups based on the mother's smoking habits. The three groups were: active smokers, passive smokers and nonsmokers. There was a significant correlation between maternal and neonatal hair concentration for both, nicotine and cotinine. Mothers and infants in the smoking groups, both active and passive, had significantly higher hair concentrations of both, nicotine and cotinine than in the control, nonsmoking group. In an older cohort, we compared two groups: 78 asthmatic children were compared to 86 healthy children exposed to similar degrees of passive smoking. By using objective, biological markers, our study aimed at verifying whether asthmatic children are different from nonasthmatic children in the way their bodies handle nicotine. Our results show, that, despite the fact that parents of asthmatic children tend to smoke a lower number of cigarettes per day, their children had an average twofold higher concentrations of cotinine in their hair then the control, nonasthmatic children. These studies document the importance of hair analysis as a tool for measuring exposure to cigarette smoke.