The prolonged elimination of nicotine in snus users has been attributed to continued absorption of nicotine released from the mucous membrane or to absorption of nicotine that has been swallowed Benowitz et al. Steady-state levels of nicotine and cotinine. The concentration of cotinine was, however, slightly higher in the snus users than in the cigarette smokers Holm et al. The same steady-state levels of nicotine and cotinine in blood as those reported by Holm et al.
There was no difference in self-assessed addiction, craving for tobacco or difficulty in giving up between snus users and cigarette smokers Holm et al. These results have recently been confirmed in a quit snus use study Gilljam et al. The nicotine uptake has often been estimated by measurement of cotinine in various body fluids. Cotinine, which is the major metabolite degradation product of nicotine, is often used as a biomarker for nicotine, since it is more stable, has a longer half-life and is easier to quantify.
Wennmalm et al. They concluded that snus users and cigarette smokers had roughly the same nicotine uptake since the level of urinary cotinine was similar. There is a tendency towards higher cotinine levels in snus users compared to smokers in some studies. This is most likely due to the fact that some nicotine is swallowed and therefore undergoes first pass metabolism to cotinine before reaching the systemic circulation Holm et al. Total daily nicotine uptake Since humans differ widely with respect to the metabolism of nicotine to cotinine and subsequent elimination of cotinine, the use of cotinine as a marker of nicotine uptake has been questioned.
A more reliable estimate of the daily uptake of nicotine from tobacco is obtained if the total amount of nicotine and its metabolites excreted into urine during 24 hours is measured. The total amount of nicotine excreted in the urine during 24 hours was measured in a group of snus users who were habitual users of a portion-packed snus containing 0.
The daily nicotine uptake was ca 25 mg in this group of snus users, who consumed 16 one-gram pinches of portion-packed snus per day. The same level was found in a group of habitual cigarette smokers, who smoked 18 cigarettes per day Andersson et al.
The daily nicotine uptake decreased to 14 mg. The same level was obtained in another group of snus users, who had been using the low nicotine snus for more than one year Andersson et al.
Few differences in tobacco product use behaviors were observed across genders or snus type, although no female respondents reported concurrent use of snus with cigars, pipe, or chewing tobacco. Several styles of pouch are available on the Swedish market.
Mini pouches tend to contain tobacco with lower moisture content than the larger pouches. The survey respondents had a general preference for the Large Normal pouches; this preference was different for female respondents, who showed greater use of Mini pouches There are also different pouch color types, the main styles being brown and white, which can result from different processing practices during the manufacture of the products.
The brown pouch products tend to have higher moisture content than the white ones due to the spraying of water during pouching. This extra process step for brown pouch products turns the pouch material from the standard white color to a brown color, which is due to staining from the tobacco. Pouch products with different pouch material colors—for example, black—are also available.
Supplementary Table 3 shows that The majority of pouched snus users in the survey However, the remainder The percentage of males and females using one to four portions concurrently is reported in Supplementary Table 4.
There was no observed trend between the pouch size and the number of pouches used concurrently, when taking into account the variation in the survey population numbers across the different pouch sizes data not shown.
The calculation for quantity of snus used per day described in the Methods section relied upon the frequent use by respondents of their main brand. In support of this, the majority The consumption results from the calculations are summarized in Table 2. Full statistical analyses are provided in Supplementary Tables 5 — Supplementary Data.
The consumption data were not normally distributed but appeared to be composed of a complex series of different distributions. Nevertheless, the consumption estimates obtained by the two different calculations were in very good agreement. By comparison, significantly higher levels of loose snus consumption were observed because the portion weights were in the order of three times greater than for pouched snus; the mean consumption of loose snus was This difference was primarily due to the larger portion size of loose snus, as the numbers of packages or portions per day were very similar for loose and pouched snus.
The data for male and female loose snus users were very similar, albeit with a very small number of female respondents in this group Table 2. Exposure time may be an important parameter influencing intake of constituents from snus. In the first stage of the survey, the respondents were asked how long, on average, they kept their portion in their mouth. Responses were limited to seven time categories ranging from less than 5 min to more than 35 min. However, it was found that the majority of respondents used the products for more than 35 min and, due to the limited scope of this question, the actual usage times of over 35 min were not specified.
Therefore, the survey was repeated with subsets of the original pouched and loose snus user survey population second and third stages of the survey, respectively, Supplementary Table 1. These later stages examined usage time by querying the shortest, average, and longest times that portions and pouches were normally kept in the mouth during use.
In each case, the respondents were asked to state the exact time in minutes. There were insufficient completed questionnaires from female loose snus users in the third stage of the survey to provide robust data for this group.
Values reported by the survey respondents were found to be nonuniformly distributed, clustering around certain time intervals—for example, 30, 45, 60, 90 min.
Table 3 shows that, on average, the normal time that respondents kept either a loose portion or a pouch in their mouths was slightly in excess of 1 hr. Full statistical analyses are provided in Supplementary Table 8. The shortest normal time of use was just over 20 min for female respondents and just over 30 min for male respondents.
Examination of the data for the longest time normally kept in mouth shows some extreme values, with male pouched snus users reporting times in mouth of up to 15 hr, and 7 hr for female pouched snus users.
All respondents, third stage of the survey recontacted users of loose snus. The third-stage, loose snus survey investigated the total fraction of the day during which the product is used Table 4.
These data are open to some degree of interpretation as to whether the respondents provided an answer which was a percentage of the day that they were awake or the total 24 hr day.
To examine this more closely, the total length of daily use time was estimated from the average normal use time per portion and the reported number of portions per day. These estimates also indicated that snus use occurs for a significant proportion of the day, with a mean value of 12— These estimates were consistent with the survey respondents reporting their total usage time as a percentage of the time they are awake; for a to hr time period, this would represent a period of 10— Due to the lack of precision in the survey question and the difficulty in obtaining realistic estimates for some survey respondents, the values for total usage time reported from this survey should be regarded as indicative estimates only.
Although most snus users maintained the portion at the site of application, a significant number, Very similar patterns of behavior were observed for both male and female users. The greater frequency of portion movement during use with pouched users may be a consequence of the integrity or shape of the pouch facilitating movement or of the relatively smaller size of pouched snus portions.
Full data on patterns of behavior for location of the portion in the mouth and incidence of portion movement during use are given in Supplementary Table Respondents who did not use snus at least daily were not included in the survey; consequently, the results may have underestimated multiple tobacco use among snus users in Sweden because, for example, smokers who occasionally used snus were not included in the dataset.
In support of this, the incidence of dual use is consistent with previous reports of low levels of regular contemporaneous snus and cigarette use in Sweden. If you make, modify, mix, manufacture, fabricate, assemble, process, label, repack, relabel, or import smokeless tobacco, you must comply with these requirements for manufacturers. This office also provides online educational resources to help regulated industry understand FDA regulations and policies.
Learn more about required warning statements and warning plans for smokeless tobacco. Note: On December 20, , the President signed legislation to amend the Federal Food, Drug, and Cosmetic Act, and raise the federal minimum age of sale of tobacco products from 18 to 21 years. It is now illegal for a retailer to sell any tobacco product — including cigarettes, cigars and e-cigarettes — to anyone under The dashed line represents the limit of quantification 0.
The study showed that systemic exposure C max , AUC 0— to nicotine from snus was dependent on the total nicotine content of the portion Figure 1 , Table 3. The AUC 0— for all six test products were ranked as: loose snus C max followed a similar ranking: loose snus Unlike the oral products, the total amount of nicotine available from the cigarette would have been limited to that inhaled by the smoker. The transfer of nicotine into smoke can be determined by machine smoking.
However, no single smoking regime can fully account for the individual and temporal variation in smoking behavior and predict exposure in all smokers. To give an indication of transfer, we measured nicotine yield with the two most commonly used smoking regimes: the ISO standard test method and Health Canada Method T, which yielded 0.
The t max for all snus products in this study was 1 hr, which was also the time of use specified in the study. In comparison, the time of use for the nicotine gum was 30 min and the t max was 0. The t max for the cigarette was considerably less at 0. The range of t max for the cigarette reported in Table 3 0.
When this subject was removed from the analysis the range was reduced to 0. Comparison of the ratios of geometric means for AUC 0— and C max for increasing nicotine content in snus showed that the increase in plasma nicotine was subproportional to the nicotine content of snus; for loose snus a 2. Similarly, for pouched snus a 1. Statistical comparisons of AUC 0—tlast and C max were made for the snus products where the protocol of use and the time of exposure were the same in all cases.
Whereas for C max , only loose snus For all snus products, the degree of irritation of lips and throat, level of salivation, or other perceived sensations such as any "buzz" feeling that subjects reported when using snus were generally low on the scale provided by the questionnaire. Overall there were no trends associated with product form or nicotine content noted in snus sensory questionnaire responses, suggesting that these product parameters had little effect on the level of sensations that subjects reported when using the snus products.
CYP2A6 genotyping classified 12 subjects as extensive metabolizers and eight subjects as intermediate metabolizers. However, due to the variability of individual exposure levels across test products for all subjects, regardless of metabolic status, the results of the genotyping analysis were not considered to have any significant impact on the interpretation of the pharmacokinetic data.
Increases from baseline systolic and diastolic blood pressure and pulse rate mean increases of 3—10 mmHg, 4—10 mmHg, and 8—13 bpm, respectively and heart rate as determined by ECG mean increases of 6—12 bpm were noted 15—30 min after product administration.
There were no apparent associations between changes in blood pressure, pulse, or heart rate and the nicotine content of the products. No serious or severe adverse events were reported during the study. In this study, we have generated new information on comparative nicotine absorption from a cigarette, loose snus, and pouched snus. The tobacco products were typical of those commercially available in Europe cigarette and Scandinavia snus at the time of the study.
In addition, nicotine absorption from use of a high-dose OTC pharmaceutical nicotine gum was measured for all subjects. Nicotine plasma levels from smoking the cigarette rose more rapidly than for the oral products, as expected from the literature Foulds et al.
The latter is an important variable; most nicotine pharmacokinetic studies on snus are based on a usage time of 30 min. However, in this study we applied the median time of 60 min reported in a survey of Swedish snus users as this was potentially more consistent with actual product use Digard et al.
These data showed that nicotine was continually absorbed from the snus portions over the entire min period, which may partly explain the usage time observed in Swedish consumers. The mean quantity of nicotine extracted from the used portions of snus and the nicotine gum followed the same trend as the pharmacokinetic AUC results and was positively correlated with the total nicotine content.
However, the AUC 0 — for the 11 mg snus was only about 1. Overall, the measured CYP2A6 metabolic status of the subjects did not have an impact on the pharmacokinetic end-points measured.
The similar nicotine pharmacokinetics for 1 g portions of loose and pouched snus, both containing similar levels of nicotine However, the data for the three different levels of total nicotine in snus indicated that the relationship was sub- proportional.
It is important to note that various behavioral factors not investigated in this study could also affect nicotine absorption such as moving the snus portion around the mouth, spitting saliva during use, or swallowing some amount of loose snus. Hence, while the protocol of use applied in this study was based on observed median usage patterns, in particular the portion sizes and min duration of use Digard et al.
There was no significant difference in self-reported sensory perceptions between any of the snus samples. However, these data were derived from a questionnaire that had been adapted for this study and not fully validated. Therefore, while this was an interesting observation further and larger studies would be required to confirm the generality of the finding. In summary, this study has provided new information on nicotine absorption for typical snus products, including loose snus, which demonstrates relationships between weight of tobacco and total nicotine content and systemic nicotine exposure.
This study also provides data on nicotine absorption for a cigarette and an OTC nicotine gum. Dr Malmqvist does not act as a consultant for British American Tobacco and has no financial interests in the Company. The authors thank the following for invaluable input and assistance: Graham Errington and Oscar M. National Center for Biotechnology Information , U.
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