A study to estimate and correlate cigarette smoke exposure in smokers in Germany as determined by filter analysis and biomarkers of exposure

A clinical study, conducted in Germany, compared two methods of estimating exposure to cigarette smoke. Estimates of mouth level exposure (MLE) to nicotine, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), pyrene and acrolein were obtained by chemical analysis of spent cigarette filters for nicotine content. Estimates of smoke constituent uptake were achieved by analysis of corresponding urinary biomarkers: for nicotine; total nicotine equivalents (nicotine, cotinine, trans-3′-hydroxycotinine plus their glucuronide conjugates), for NNK; (4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) plus glucuronide, for pyrene; 1-hydroxy pyrene (1-OHP) plus glucuronide and for acrolein; 3-hydroxylpropyl-mercapturic acid (3-HPMA) plus the nicotine metabolite cotinine in plasma and saliva. Two hundred healthy volunteer subjects were recruited; 50 smokers of each of 1–2 mg, 4–6 mg and 9–10 mg ISO tar yield cigarettes and 50 non-smokers (NS). Smokers underwent two periods of home smoking, each followed by residence in a clinic. Smoking was permitted ad libitum, and spent cigarette filters, cigarette consumption data, 24 h urine, as well as plasma and saliva samples were collected. Significant correlations (p < 0.001) were found between MLE and the relevant biomarker for each smoke constituent. The Pearson correlation coefficients (r) were 0.83 (nicotine), 0.76 (NNK), 0.82 (acrolein) and 0.63 (pyrene). Mean MLE estimates for nicotine, NNK and pyrene showed a dose response in line with ISO tar yield smoked, with 10 mg > 4 mg > 1 mg, and for acrolein 10 mg > 4 mg > *1 mg (where * indicates not significant at 95% confidence level). The mean exposure estimates from biomarkers for nicotine, NNK and acrolein also showed a dose response in line with ISO tar yield with 10 mg > 4 mg > 1 mg > NS, and for pyrene 10 mg > *4 mg > 1 mg > NS. This study shows that estimates of exposure obtained by filter analysis and biomarkers of exposure correlate significantly over a wide range of smoke exposures and that filter analysis may provide a simple and effective alternative to biomarkers for estimating smokers’ exposure.     

Scientific assessment of the use of sugars as cigarette tobacco ingredients: a review of published and other publicly available studies

Sugars, such as sucrose or invert sugar, have been used as tobacco ingredients in American-blend cigarettes to replenish the sugars lost during curing of the Burley component of the blended tobacco in order to maintain a balanced flavor. Chemical-analytical studies of the mainstream smoke of research cigarettes with various sugar application levels revealed that most of the smoke constituents determined did not show any sugar-related changes in yields (per mg nicotine), while ten constituents were found to either increase (formaldehyde, acrolein, 2-butanone, isoprene, benzene, toluene, benzo[k]fluoranthene) or decrease (4-aminobiphenyl, N-nitrosodimethylamine, N-nitrosonornicotine) in a statistically significant manner with increasing sugar application levels. Such constituent yields were modeled into constituent uptake distributions using simulations of nicotine uptake distributions generated on the basis of published nicotine biomonitoring data, which were multiplied by the constituent/nicotine ratios determined in the current analysis. These simulations revealed extensive overlaps for the constituent uptake distributions with and without sugar application. Moreover, the differences in smoke composition did not lead to relevant changes in the activity in in vitro or in vivo assays. The potential impact of using sugars as tobacco ingredients was further assessed in an indirect manner by comparing published data from markets with predominantly American-blend or Virginia-type (no added sugars) cigarettes. No relevant difference was found between these markets for smoking prevalence, intensity, some markers of dependence, nicotine uptake, or mortality from smoking-related lung cancer and chronic obstructive pulmonary disease. In conclusion, thorough examination of the data available suggests that the use of sugars as ingredients in cigarette tobacco does not increase the inherent risk and harm of cigarette smoking.     

Emergence of electronic cigarette use in US adolescents and the link to traditional cigarette use

BackgroundElectronic cigarettes (e-cigarettes) are increasingly used by US adolescents and may be a gateway to traditional cigarette use. We examine rates of both products by age and examine differences in age-varying rates by sex and race/ethnicity.MethodsData are from the 2014 National Youth Tobacco Survey, a national sample of US middle and high school students (n = 22.007); students ages 11–19 were included. Past 30-day e-cigarette and traditional cigarette use were examined as a function of age; sex and race/ethnicity were included as moderators. The age-varying association between e-cigarette and traditional cigarette use was also examined.ResultsRates of e-cigarette use increase faster than traditional cigarette use from ages 13–16. Compared to females, males had higher rates of e-cigarette use from ages 14–17.5 and traditional cigarette use from ages 15–18. Between ages 12–14, more Hispanic adolescents used e-cigarettes compared to White or Black adolescents; after age 14 Hispanics and Whites reported similar rates, peaking at twice the rate for Blacks. Hispanic adolescents report greater traditional cigarette use versus Whites between ages 12–13, but lower rates between ages 15–18. E-cigarette use was strongly associated with traditional cigarette use, particularly during early adolescence [OR > 40 before age 12].ConclusionsYoung Hispanic adolescents are at elevated risk for use of e-cigarettes and traditional cigarettes during early adolescence. During early adolescence, youth using e-cigarettes are more likely to smoke traditional cigarettes compared to youth not using e-cigarettes. The study of age-varying effects holds promise for advancing understanding of disparities in health risk behaviors.     

Evaluation of a low to middle tar/medium nicotine cigarette designed to maintain nicotine delivery to the smoker

A specific objective of this 6-week crossover study was to determine how 21 regular smokers of middle tar cigarettes changed their smoking behaviour and uptake of smoke constituents, when switching to either lower tar cigarettes capable of delivering amounts of nicotine similar to a conventional middle tar cigarette (maintained nicotine product), or to conventional low tar/low nicotine cigarettes. Subjects visited the laboratory every 2 weeks for detailed assessment of their smoking behaviour. Weekly per capita consumption was similar for all three cigarettes. They were smoked with variable intensities (low tar > maintained nicotine > middle tar), the tendency being for larger puff volumes, faster puffing and increased puff duration with the low tar cigarettes. The maintained nicotine cigarette was preferred to the middle tar cigarette, although acceptability ratings of the three cigarettes only differed marginally. The nicotine absorbed from the maintained nicotine and middle tar cigarettes was similar and significantly greater than the levels achieved from the low tar cigarettes. Intake of carbon monoxide into the mouth and absorption into the blood stream was lower for the maintained nicotine cigarette than for the middle tar cigarette, with the low tar cigarette occupying an intermediate position. Derived estimates of tar intake suggested reduced intake of tar into the respiratory tract (around 25%) from the maintained nicotine product relative to the middle tar product. The possible advantages of switching to maintained nicotine cigarettes is discussed.     

Damage to human alpha-1-proteinase inhibitor by aqueous cigarette tar extracts and the formation of methionine sulfoxide.

The effects of aqueous extracts of cigarette tar (ACT) on human alpha-1-proteinase inhibitor (alpha 1PI) are examined by determining alterations in the elastase inhibitory capacity (EIC), amino acid residue content, and electrophoretic behavior of the protein. Hydrogen peroxide generated in ACT by autoxidative processes accounts for the major portion of the loss of EIC. This is indicated by several lines of evidence, including the fact that anaerobic incubations of ACT with alpha 1PI cause negligible loss of EIC. The hydrogen peroxide content of the ACT was estimated by measuring the ability of the extracts to oxidize methionine to methionine sulfoxide; hydrogen peroxide concentrations that model those in ACT cause a similar loss in EIC. Exposure of alpha 1PI to ACT leads to methionine sulfoxide as the only detectable amino acid residue modification and explains the loss of EIC. This is the first report to directly demonstrate methionine sulfoxide formation in alpha 1PI exposed to cigarette smoke components in vitro. Similar amounts of methionine sulfoxide are found in alpha 1PI exposed to hydrogen peroxide at the concentrations predicted to be formed in ACT. Nondenaturing PAGE reveals that alpha 1PI exposed to ACT, but not hydrogen peroxide, shows changes in electrophoretic behavior; the changes are nonoxidative in nature and are not related to the loss of EIC. Studies on the effect of chelators on ACT-mediated damage to alpha 1PI indicate some role for metal ions; however, none of the chelators completely protect alpha 1PI.(ABSTRACT TRUNCATED AT 250 WORDS)     

Puff-by-puff sensory evaluation of a low to middle tar medium nicotine cigarette designed to maintain nicotine delivery to the smoker

Puff-by-puff assessments of a range of sensory and subjective attributes were made for three cigarettes, with tar and nicotine yields of: 10.0 and 1.4; 17.0 and 1.7; and 8.8 and 0.8 mg/cigarette, respectively. Seven attributes were assessed: mouth impact, throat impact, chest effect, roughness, intensity of flavour, satisfaction and quality of flavour. Significant differences between the three cigarettes were obtained for most of these attributes. Principal component analysis of the data revealed three principal components related to the cigarettes under investigation. Components 1 and 2 accounted for approximately 47 and 28% of the total variance and component 3 only added a further 7%. Principal component 1 was a complex combination of intensity-related characteristics, i.e. mouth and throat impact, chest effect, intensity of flavour, roughness, while quality of flavour and satisfaction contributed to the separation of samples on principal component 2. However, the two major components could not be defined simply in terms of the yields of tar and nicotine for the products determined on a smoking machine.     

Scientific assessment of the use of sugars as cigarette tobacco ingredients: A review of published and other publicly available studies

Sugars, such as sucrose or invert sugar, have been used as tobacco ingredients in American-blend cigarettes to replenish the sugars lost during curing of the Burley component of the blended tobacco in order to maintain a balanced flavor. Chemical-analytical studies of the mainstream smoke of research cigarettes with various sugar application levels revealed that most of the smoke constituents determined did not show any sugar-related changes in yields (per mg nicotine), while ten constituents were found to either increase (formaldehyde, acrolein, 2-butanone, isoprene, benzene, toluene, benzo[k]fluoranthene) or decrease (4-aminobiphenyl, N-nitrosodimethylamine, N-nitrosonornicotine) in a statistically significant manner with increasing sugar application levels. Such constituent yields were modeled into constituent uptake distributions using simulations of nicotine uptake distributions generated on the basis of published nicotine biomonitoring data, which were multiplied by the constituent/nicotine ratios determined in the current analysis. These simulations revealed extensive overlaps for the constituent uptake distributions with and without sugar application. Moreover, the differences in smoke composition did not lead to relevant changes in the activity in in vitro or in vivo assays. The potential impact of using sugars as tobacco ingredients was further assessed in an indirect manner by comparing published data from markets with predominantly American-blend or Virginia-type (no added sugars) cigarettes. No relevant difference was found between these markets for smoking prevalence, intensity, some markers of dependence, nicotine uptake, or mortality from smoking-related lung cancer and chronic obstructive pulmonary disease. In conclusion, thorough examination of the data available suggests that the use of sugars as ingredients in cigarette tobacco does not increase the inherent risk and harm of cigarette smoking.     

Neurobehavioral assessment: a survey of use and value in safety assessment studies.

This report describes the results of a survey designed to evaluate the contribution of F1 neurobehavioral testing to hazard identification and characterization in safety assessment studies. (To review the details of the distributed survey, please see the supplementary data for this article on the journal's Web site.) The survey provided information about studies completed in industrial laboratories in the United States, Europe, and Japan since 1990 on 174 compounds. The types of compounds included were pharmaceutical (81%), agricultural (7%), industrial (1%), or were undefined (10%). Information collected included the intended use of the test agent, general study design and methodology, the types and characteristics of F1 behavioral evaluations, and the frequency with which agents affected neurobehavioral parameters in comparison to other F0 and F1 generation parameters. F1 general toxicology parameters such as mortality, pre- and postweaning body weight, and food intake were assessed in most studies and were affected more frequently than other parameters by the test agents. F1 behavioral parameters were assessed less consistently across studies, and were less frequently affected by the agents tested. Although affected by agents less often than general toxicology parameters, F1 behavioral parameters along with other parameters defined the no-observed-effect level (NOEL) in 17/113 (15%) of studies and solely defined the NOEL in 3/113 (2.6%) of studies. Thus, F1 behavioral parameters sometimes improved on the standard toxicological measures of hazard identification. While not detecting agent effects as readily as some measures, the F1 behavioral parameters provide information about agent effects on specialized functions of developing offspring not provided by other standard measures of toxicity. The survey results emphasize the need for further research into the methods of behavioral assessment as well as the mechanisms underlying the neurobehavioral alterations.     

Augmentation of elastase-induced emphysema by cigarette smoke: effects of reducing tar and nicotine content

The effects of reducing the tar and nicotine concentration of cigarette smoke were examined in a rat model of smoke-augmented, porcine pancreatic elastase- (PPE-) induced, pulmonary emphysema. Sixty-eight female Long-Evans rats were divided approximately evenly into seven groups: control, PPE, PPE plus sham smoke, high-tar/nicotine cigarette smoke (2R1; 38.8 mg total particulate matter and 2.2 mg nicotine per cigarette), low-tar/nicotine cigarette smoke (1R4F; 10.8 mg total particulate matter and 0.8 mg nicotine per cigarette), PPE + 2R1, and PPE + 1R4F. Three days after intratracheal administration of PPE (400 IU/kg), animals in the smoke-treated groups were exposed to 8-10 puffs of cigarette smoke daily, 7 d/wk for 12 wk. Sham-treated animals received room air in place of cigarette smoke. At the conclusion of the exposures, pulmonary function tests were performed under general anesthesia. Cigarette-smoke exposure alone did not produce significant changes in pulmonary function. Elastase-treated groups demonstrated significant increases in total lung capacity, functional residual capacity, and dynamic and static compliance, as well as significant decreases in carbon monoxide (CO) diffusing capacity and CO diffusion coefficient. Morphometric measurements of mean linear intercept demonstrated a loss of alveolar fine structure with enlargement of distal airspaces in PPE-treated rats. Exposure to either 2R1 or 1R4F cigarette smoke significantly enhanced many of the emphysematous changes produced by PPE, but there were no significant differences between the effects of the two smokes. These data indicate that reducing the tar and nicotine concentration of cigarette smoke does not lessen its ability to augment PPE-induced pulmonary emphysema in the rat.     

Chewing tobacco use by adolescents: Prevalence and relation to cigarette smoking

The prevalence of teenage smokeless tobacco use and its relation to cigarette smoking was studied. Nine percent of 7th grade boys and 20% of 9th and 10th grade boys reported daily use. There was very little regular chewing among girls although about 20% reported having tried it. There was a strong association between smoking and chewing among 7th graders but only a weak association among 9th and 10th graders. Boys who chew tended to have friends who chew and/or smoke. The data suggested that chewing is affected by peer social influence processes in a manner similar to smoking.     

Relationship between cigarette format and mouth-level exposure to tar and nicotine in smokers of Russian king-size cigarettes

Differences in length and circumference of cigarettes may influence smoker behaviour and exposure to smoke constituents. Superslim king-size (KSSS) cigarettes (17 mm circumference versus 25 mm circumference of conventional king-size [KS] cigarettes), have gained popularity in several countries, including Russia. Some smoke constituents are lower in machine-smoked KSSS versus KS cigarettes, but few data exist on actual exposure in smokers. We investigated mouth-level exposure (MLE) to tar and nicotine in Russian smokers of KSSS versus KS cigarettes and measured smoke constituents under machine-smoking conditions. MLE to tar was similar for smokers of 1 mg ISO tar yield products, but lower for smokers of 4 mg and 7 mg KSSS versus KS cigarettes. MLE to nicotine was lower in smokers of 4 mg KSSS versus KS cigarettes, but not for other tar bands. No gender differences were observed for nicotine or tar MLE. Under International Organization for Standardization, Health Canada Intense and Massachusetts regimes, KSSS cigarettes tended to yield less carbon monoxide, acetaldehyde, nitric oxide, acrylonitrile, benzene, 1,3-butadiene and tobacco-specific nitrosamines, but more formaldehyde, than KS cigarettes. In summary, differences in MLE were observed between cigarette formats, but not systematically across pack tar bands.     

Application of the "filter model" to a risk assessment for vinyl chloride

The filter model was used to estimate thresholds for the induction of cancer from many dose-response sets for inhalation and ingestion exposure to vinyl chloride for rat and inhalation exposure for mouse. Estimates for a variety of end-point combinations were log-normally distributed over about 2 decades from about 1 to 100 ppm for inhalation exposure to rat and 0.1 to 30 ppm for mouse. When the data is transformed to "dose" (milligrams per kilogram body weight per day), the estimates for inhalation and ingestion exposure and also for rat and mouse are similar. Estimates for different experiments carried out for different durations of time (single exposure to 1 yr) are comparable. Since the threshold is an intrinsic property of the biological system, the estimate, even from a protocol for short exposure and less than lifetime observation, can be used directly in a risk assessment as the maximum safe dose.     

Electronic cigarette use after the adoption of a tobacco-free campus policy

Electronic (e)-cigarette use has increased markedly across groups in the past few years. For this reason, risk factors associated with e-cigarette use warrant further research. This study presents secondary data analyses on e-cigarette use from a large cross-sectional database assessing attitudes toward a tobacco-free campus (TFC) policy prior to policy implementation (n = 1188), one-month post policy (n = 1442), and one-year post policy(n = 1125). Students from a U.S. university located on the border with Mexico (M_age = 25.02 years, SD = 7.99; 59.2% female) were recruited via email to complete an online assessment of their tobacco use, attitudes toward TFC policies, perceived problematic tobacco use, and knowledge of tobacco use risk. The prevalence of any past-30-day e-cigarette use significantly increased from 4.4% to 26.6% between baseline and one-month post-policy, and reduced to 17.3% between one-month post-policy and one-year post policy. Weekly alcohol use was associated with e-cigarette use at each assessment point. There was some evidence of higher e-cigarette use among younger students and current smokers. Additional studies are needed to understand the influence of comprehensive TFC policies on both e-cigarette use and polysubstance use (i.e., alcohol and combustible cigarettes).     

Comparison of different exposure assessment methods to estimate the long-term dietary exposure to dioxins and ochratoxin A

Long-term exposures to dioxins (PCCD/F and dioxin-like PCBs) and ochratoxin A were calculated using food consumption data of the European concise database combined with concentration data of the Netherlands (NL) using a deterministic approach. To refine these assessments, exposures were also calculated using three long-term exposure models, observed individual means (OIM), Iowa State University Foods (ISUF), and betabinomial-normal (BBN) models, combined with individual food consumption data of NL. BBN and ISUF correct the variation in long-term exposure for the within-person variation, whereas OIM calculates the mean exposure over the days in the food consumption survey. Exposures obtained with the concise database were highest, and those obtained with OIM higher than with BBN and ISUF. Contribution of the major sources of exposure differed between the concise database and the three models. Given the constraints of the concise database, exposures obtained with this database should be interpreted as a first tier assessment. Preferably, refined assessments using models that correct the variation in long-term exposure for the within-person variation combined with individual food consumption data and national concentration data should be used to assess the long-term exposure. We recommend the use of BBN since it can model exposure distributions that depend on covariates.     

Competitive inhibition by inducer as a confounding factor in the use of the ethoxyresorufin-O-deethylase (EROD) assay to estimate exposure to dioxin-like compounds.

The ethoxyresorufin-O-deethylase (EROD) assay has been extensively used in whole animals and in cell culture as a biomarker of exposure to environmental contaminants such as dioxin-like compounds (DLCs). This paper addresses two controversial phenomena that arise when DLCs are examined by the EROD assay. Firstly, the maximum level of induced EROD activity varies with the identity of the inducing compound; secondly, the induced EROD activity reaches a concentration-dependent maximum level that is followed by an apparent reduction in activity when the concentration of inducer is further increased. These phenomena are completely explained by competitive inhibition of the EROD enzyme-substrate reaction by the dioxin-like compound. A kinetic model explains the biphasic appearance of EROD induction curves as a function of a compound's binding affinity with the Ah receptor (Kd) and its binding affinity to CYP 1A1 (Ki) which results in inhibition of the EROD enzyme-substrate reaction. These results limit the reliability of the information obtained from calibration curves of EROD activity versus concentration of a standard DLC such as 2,3,7,8-tetrachlorodibenzo-p-dioxin.     

Aspects of the design protocol and the statistical methods for analysis of tar,nicotine and carbon monoxide yields in cigarette smoke that can affect the measurement variability within collaborative studies

Statistical principles described in ISO 5725–1 (1994) are a robust basis for evaluating cigarette smoke data from collaborative studies under the ISO 3308 machine smoking and for specifying the criteria for the removal of outlier data and determination of mean yields and their variability. However, the standard only provides recommendations on outlier removal that should be taken into account by experts who undertake data interpretation. The potential for over-interpretation of data from small numbers of laboratories is highlighted and recommendations made to deal with this possibility.