The effect of cigarette burn time on exposure to nicotine and carbon monoxide in adult smokers

Cigarette burn time (CBT), conventionally defined as the time a cigarette burns during smoking, can be affected by cigarette design and smoking behavior. A previous study showed a strong negative correlation between CBT and nicotine yield under machine smoking conditions. This study for the first time examined the relationship of CBT and exposure to nicotine and carbon monoxide in adult smokers in a controlled clinical study. 24h nicotine equivalents excretion (NE), carboxyhemoglobin (COHb) and CBT were measured in two groups of 20 adults smoking Marlboro Lights and 20 adults smoking Marlboro Ultra on two consecutive days. Approximately 20% of the total variability in CBT was attributed to cigarette brand, 34% to smokers and 1% to study day. The exposure index, defined as the number of cigarettes smoked per day divided by average daily CBT for each smoker, accounted for a large proportion of the total variability in NE (R(2)=0.79-0.91) and COHb (R(2)=0.85-0.90). We conclude that CBT has an important influence on levels of NE and COHb in adult smokers. CBT, along with the number of cigarettes smoked per day, can be used to estimate adult smokers' exposure to nicotine and carbon monoxide.     

Factors affecting exposure to nicotine and carbon monoxide in adult cigarette smokers

Exposure to cigarette smoke among smokers is highly variable. This variability has been attributed to differences in smoking behavior as measured by smoking topography, as well as other behavioral and subjective aspects of smoking. The objective of this study was to determine the factors affecting smoke exposure as estimated by biomarkers of exposure to nicotine and carbon monoxide (CO). In a multi-center cross-sectional study of 3585 adult smokers and 1077 adult nonsmokers, exposure to nicotine and CO was estimated by 24 h urinary excretion of nicotine and five of its metabolites and by blood carboxyhemoglobin, respectively. Number of cigarettes smoked per day (CPD) was determined from cigarette butts returned. Puffing parameters were determined through a CreSS® micro device and a 182-item adult smoker questionnaire (ASQ) was administered. The relationship between exposure and demographic factors, smoking machine measured tar yield and CPD was examined in a statistical model (Model A). Topography parameters were added to this model (Model B) which was further expanded (Model C) by adding selected questions from the ASQ identified by a data reduction process. In all the models, CPD was the most important and highest ranking factor determining daily exposure. Other statistically significant factors were number of years smoked, questions related to morning smoking, topography and tar yield categories. In conclusion, the models investigated in this analysis, explain about 30-40% of variability in exposure to nicotine and CO.     

A randomized, controlled exposure study in adult smokers of full flavor Marlboro cigarettes switching to Marlboro Lights or Marlboro Ultra Lights cigarettes

Rationale. To date no state-of-the-art clinical study has been conducted to address the question as to whether switching to lower tar cigarettes reduces exposure to smoke constituents in humans. Methods. Randomized, controlled, forced switching study in 225 adult smokers of full flavor Marlboro (MFF) cigarettes for 8 days with a 24-week follow-up. Subjects smoked MFF (a 15-mg Federal Trade Commission (FTC) tar cigarette) at baseline and were randomized to smoke 11-mg Marlboro Lights (ML) or 6-mg Marlboro Ultra Lights (MUL) cigarettes. Biomarkers of exposure to nicotine, 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), pyrene, CO, benzene, acrolein, and mutagenic substances were measured. Results. In the short-term phase, switching from MFF to ML showed statistically significant decreases in nicotine exposure (-13%) and non-significant increases in CO exposure (+6%), while switching from MFF to MUL showed statistically significant decreases in nicotine (-27%) and CO (-13%) exposure. Both nicotine and CO biomarkers trended similarly in the 24-week follow-up as in the short-term phase. The other biomarkers of cigarette smoke constituents followed the same trend as nicotine at the end of the 24-week follow-up. Conclusions. Switching smokers to lower FTC tar yield cigarettes, on average, reduces nicotine and other biomarkers considered surrogates of tar exposure.     

Lack of effect of menthol level and type on smokers’ estimated mouth level exposures to tar and nicotine and perceived sensory characteristics of cigarette smoke

Menthol can reduce sensory irritation and it has been hypothesised that this could result in smokers of mentholated cigarettes taking larger puffs and deeper post-puff inhalations thereby obtaining higher exposures to smoke constituents than smokers of non-mentholated cigarettes. The aim of our study was to use part-filter analysis methodology to assess the effects of cigarette menthol loading on regular and occasional smokers of mentholated cigarettes. We measured mouth level exposure to tar and nicotine and investigated the effects of mentholation on smokers’ sensory perceptions such as cooling and irritation. Test cigarettes were produced containing no menthol and different loadings of synthetic and natural l-menthol at 1 and 4 mg ISO tar yields. A target of 100 smokers of menthol cigarettes and 100 smokers who predominantly smoked non-menthol cigarettes from both 1 and 4 mg ISO tar yield categories were recruited in Poland and Japan. Each subject was required to smoke the test cigarette types of their usual ISO tar yield. There were positive relationships between menthol loading and the perceived ‘strength of menthol taste’ and ‘cooling’ effect. However, we did not see marked menthol-induced reductions in perceived irritation or menthol-induced increases in mouth level exposure to tar and nicotine.     

The relationship between nicotine dependence scores and biomarkers of exposure in adult cigarette smokers

Background: Tobacco dependence is a multidimensional phenomenon. The Fagerström Test for Nicotine Dependence (FTND) is a widely administered six-item questionnaire used as a measure of nicotine dependence. It has been suggested that this test may not represent the entire spectrum of factors related to dependence. Also the relationship of this test with biomarkers of exposure to cigarette smoke has not been extensively studied. Methods: Data from a multi-center, cross-sectional, ambulatory study of US adult smokers (the Total Exposure Study, TES) was analyzed. The FTND score and a number of additional questions related to smoking behavior, from an adult smoker questionnaire (ASQ) completed by 3585 adult smokers in the TES were analyzed. The 24-h urine nicotine equivalents, serum cotinine and blood carboxyhemoglobin were measured as biomarkers of exposure (BOE) to nicotine and carbon monoxide. Cigarette butts returned were collected during the 24-h urine collection period. Results: The FTND showed moderate correlations with BOE, while selected questions from ASQ although statistically significant, had weaker correlations. FTND scores showed substantially weaker correlations without the question about cigarettes smoked per day (CPD). CPD and time to first cigarette (TTFC) had the most impact on BOE. Conclusion: Additional questions from ASQ did not appear to contribute towards refining the FTND test. The correlation of the FTND scores with nicotine and carbon monoxide seems to be primarily driven by CPD. CPD and TTFC were the most important factors correlating with exposure.     

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.     

Exposure to and deposition of fine and ultrafine particles in smokers of menthol and nonmenthol cigarettes

Introduction: Research on the deposition of mainstream smoke particulate in the respiratory tract of smokers is needed to understand how exposure may vary based on cigarette menthol content.

Methods: We conducted a nine-participant crossover study in which smokers were randomly assigned to cigarettes differing primarily in menthol content. Participants smoked the test cigarettes ad libitum for one week, provided spot urine samples, and then smoked four test cigarettes in a laboratory session; this was repeated for the other test cigarette in week two. Fine and ultrafine particulate matter in exhaled breath were characterized, and smoking behavior was monitored. Participant-specific mainstream smoke, generated using each participant’s topography data, was characterized. During home smoking, participants collected their spent test cigarette butts for estimates of mouth-level exposures (MLE) to mainstream nicotine and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK).

Results: Participant-specific mainstream smoke NNK was higher (39%) and daily MLE to NNK was also higher (52%) when participants smoked the menthol cigarette. Nicotine was not significantly different. Participants retained more ultrafine particulate (43%) and fine particulate benzo(a)pyrene (43%) when smoking the menthol cigarette. There were no significant differences in the levels of urinary biomarkers for nicotine, NNK, or pyrene.

Conclusion: This study demonstrates the use of noninvasive real-time techniques to measure exposure differences between cigarettes differing primarily in menthol content. Differences between NNK exposure, ultrafine particle and benzo(a)pyrene deposition, and smoking behavior were observed. Additional research using these techniques with cigarettes that differ only in menthol content is required to unequivocally attribute the exposure differences to presence or absence of menthol.     

Unpacking the association: Individual differences in the relation of prenatal exposure to cigarettes and disruptive behavior phenotypes

Prenatal exposure to cigarettes has been robustly associated with disruptive behavior in diverse samples and across developmental periods. In this paper we aim to elucidate exposure related behavioral phenotypes and developmental pathways by testing: (a) differential associations of exposure and four disruptive behavior dimensional phenotypes: Aggression, Noncompliance, Temper Loss and Low Concern for Others; and (b) moderation of these pathways including sex differences and moderation by parental responsive engagement. Participants were 211 teens and their parents from the East Boston Family Study (EBFS), an adolescent follow-up of a pregnancy cohort over-sampled for exposure. A best estimate serum cotinine corrected score was used to characterize exposure. In multivariate models controlling for parental antisocial behavior, family adversity and secondhand exposure, exposure uniquely predicted Aggression and Noncompliance. Paternal responsiveness moderated exposure effects on disruptive behavior. There were no sex differences in these patterns. Phenotypic findings suggest the possibility of specific neural mechanisms. In conjunction with prior research, protective effects of parental responsiveness occurring as late as adolescence point to the potential benefit of parenting-based prevention efforts to reduce risk to exposed offspring.     

Comparison of expired carbon monoxide and plasma cotinine as markers of cigarette abstinence

The clinical pharmacology of biochemical measures of nicotine exposure has been thoroughly reviewed with regard to usefulness and limitations in detecting abstinence from cigarette smoking. While plasma nicotine concentration measures only acute nicotine exposure, plasma, salivary, and urine cotinine concentrations reflect exposure over an extended period of time. Although, expired carbon monoxide (CO) is frequently used to confirm self reports, it has a relatively short half life, calling into question whether this measure might provide misleading information by exaggerating smoking cessation success rates. To examine this question, we analyzed expired CO, plasma cotinine and self report data collected in a clinical trial in which subjects (N=207) were randomly assigned to gain- or loss-framed messages for smoking cessation in combination with open label sustained-release bupropion (300 mg/day). In examining measurements collected at 6 weeks, 3 and 6 months, results showed that CO significantly overestimated abstinence rates as compared with cotinine, although the discrepancy was less at the later time points. These data suggest that while expired CO is a useful and well-established marker in certain contexts, when testing extended abstinence from smoking with non-nicotine medications, cotinine measurements should be preferred.     

Effects of fetal and neonatal exposure to nicotine on blood pressure and perivascular adipose tissue function in adult life

In Wistar rats, maternal exposure to nicotine was shown to impair the inhibitory function of perivascular adipose tissue on vascular contractility in the aorta of the offspring. It is not known whether an impairment of perivascular adipose tissue function occurs in smaller arteries, and whether the control of blood pressure is affected. Here we studied the blood pressure effects and the alteration of perivascular adipose tissue function in mesenteric arteries of the offspring born to Wistar-Kyoto rat (WKY) dams exposed to nicotine. Nulliparous female WKY rats were given either nicotine bitartrate (1 mg/kg/day) or saline (vehicle) by subcutaneous injection 2 weeks prior to mating, during pregnancy and until weaning. Blood pressure of the offspring and functional studies with mesenteric arteries were conducted. Tissue samples (thoracic aorta, mesenteric arteries, and kidneys) were collected for morphological and immunohistochemical examinations. Blood pressure increased from 14 weeks of age onwards in the offspring born to nicotine-exposed dams. Nicotine-exposed offspring showed a significant increase in the number of brown adipocytes in aortic perivascular adipose tissue relative to control offspring. In mesenteric arteries from control offspring, contractile responses induced by phenylephrine, serotonin, and 9,11-dideoxy-11alpha, 9alpha-epoxymethanoprostaglandin F(2)alpha (U44619) were significantly attenuated in the presence of perivascular adipose tissue, an effect not observed in the nicotine-exposed tissues. Endothelium-dependent relaxation responses to carbachol, kidney weight, the total number of nephrons and glomerulus' size were comparable in nicotine and saline groups. We conclude that fetal and neonatal exposure to nicotine caused blood pressure elevation. Alterations in perivascular adipose tissue composition and modulatory function are some of the mechanisms associated with this blood pressure increase.     

Effect of prolonged exposure to nicotine and stress on the pituitary-adrenocortical response; the possibility of cross-adaptation

Daily IP injections of nicotine (200 μg/kg body weight) resulted in an adaptation of the nicotine induced rise in plasma corticosterone. By 30 days the plasma corticosterone rise was not significantly different from that seen in control animals receiving an injection of saline. A similar adaptation to the plasma corticosterone response to the stress of signalled, irregular footshock was also observed. However, in the case of the exposure to stress, while the corticosterone response at day 40 was significantly less than the response seen on day 1, it was still significantly greater than the plasma corticosterone level from unstressed control animals. Cross-adaptation experiments were conducted in which animals were adapted to the steroidogenic action of nicotine and then subjected to a novel exposure to footshock stress, and vice versa. In both situations the animals responded to the novel stimulus, either stress or nicotine, with a significant rise in plasma corticosterone. It was postulated that nicotine and psychological stress act upon the hypothalamo-pituitary-adrenal axis via functionally separate pathways at the level of the corticotrophin releasing factor neuron. The separate pathways appear to differ in their ability to be inhibited by corticosterone feedback.     

Reductions in biomarkers of exposure (BoE) to harmful or potentially harmful constituents (HPHCs) following partial or complete substitution of cigarettes with electronic cigarettes in adult smokers

Changes in fifteen urine, blood and exhaled breath BoEs of HPHCs representing classes of compounds reported by FDA to be significant contributors to smoking-associated disease risks were measured in 105 clinical-confined subjects following randomization and a five-day forced-switch from usual brand conventional combustible cigarettes to: (i) exclusive commercial e-cigarette use; (ii) dual-use of commercial e-cigarettes and the subject’s usual cigarette brand; or (iii) discontinued use of all tobacco or nicotine products. Levels of urinary biomarkers in subjects that completely substituted their usual cigarette with e-cigarettes were significantly lower (29–95%) after 5 days. Percent reductions in eight of nine urinary BoEs were indistinguishable to smokers who had quit smoking, except for nicotine equivalents, which declined by 25–40%. Dual users who halved self-reported daily cigarette consumption with e-cigarettes exhibited reductions (7–38%) in eight of nine urinary biomarkers, but had increase (1–20%) in nicotine equivalents. Reductions were broadly proportional to the reduced numbers of cigarettes smoked. Dual user urinary nicotine equivalents were slightly higher, but not statistically significant. After 5 days, blood nicotine biomarker levels were lower in the cessation (75–96%) and exclusive use groups (11–83%); with dual users experiencing no significant reductions. All subjects experienced significant decreases in exhaled CO. Decreases in the cessation and exclusive groups ranged from 88–89% and 27–32% in dual users. Exhaled NO increased in the cessation and exclusive groups (46–63% respectively), whereas the dual users experienced minimal changes. Overall, smokers who completely or partially substituted conventional cigarettes with e-cigarettes over five days, experienced reductions in HPHCs.     

The effect of carbon monoxide exposure on morphology of lungs and pulmonary arteries in rabbits

Rabbits were continously exposed either to 200 parts per million carbon monoxide for 3, 4, and 6 weeks or to 1,900 parts per million carbon monoxide for 5 h. Blind light and transmission electron microscopic investigations showed no morphological changes in the lung parenchyma, lung vasculature or in pulmonary arteries of the exposed animals when compared with controls. The discrepancies with findings previously reported by other authors are discussed.This work was supported by Forschungsgesellschaft Rauchen und Gesundheit, Hamburg, Federal Republic of Germany     

Integration of mechanistic and pharmacokinetic information to derive oral reference dose and margin‐of‐exposure values for hexavalent chromium

The current US Environmental Protection Agency (EPA) reference dose (RfD) for oral exposure to chromium, 0.003 mg kg^?1 day^?1, is based on a no‐observable‐adverse‐effect‐level from a 1958 bioassay of rats exposed to ≤25 ppm hexavalent chromium [Cr(VI)] in drinking water. EPA characterizes the confidence in this RfD as “low.” A more recent cancer bioassay indicates that Cr(VI) in drinking water is carcinogenic to mice at ≥30 ppm. To assess whether the existing RfD is health protective, neoplastic and non‐neoplastic lesions from the 2 year cancer bioassay were modeled in a three‐step process. First, a rodent physiological‐based pharmacokinetic (PBPK) model was used to estimate internal dose metrics relevant to each lesion. Second, benchmark dose modeling was conducted on each lesion using the internal dose metrics. Third, a human PBPK model was used to estimate the daily mg kg^?1 dose that would produce the same internal dose metric in both normal and susceptible humans. Mechanistic research into the mode of action for Cr(VI)‐induced intestinal tumors in mice supports a threshold mechanism involving intestinal wounding and chronic regenerative hyperplasia. As such, an RfD was developed using incidence data for the precursor lesion diffuse epithelial hyperplasia. This RfD was compared to RfDs for other non‐cancer endpoints; all RfD values ranged 0.003–0.02 mg kg^?1 day^?1. The lowest of these values is identical to EPA's existing RfD value. Although the RfD value remains 0.003 mg kg^?1 day^?1, the confidence is greatly improved due to the use of a 2‐year bioassay, mechanistic data, PBPK models and benchmark dose modeling.     

Using expired air carbon monoxide to determine smoking status during pregnancy: Preliminary identification of an appropriately sensitive and specific cut-point

Background

Measurement of carbon monoxide in expired air samples (ECO) is a non-invasive, cost-effective biochemical marker for smoking. Cut points of 6 ppm–10 ppm have been established, though appropriate cut-points for pregnant woman have been debated due to metabolic changes. This study assessed whether an ECO cut-point identifying at least 90% of pregnant smokers, and misidentifying fewer than 10% of non-smokers, could be established.

Methods

Pregnant women (N = 167) completed a validated self-report smoking assessment, a urine drug screen for cotinine (UDS), and provided an expired air sample twice during pregnancy.

Results

Half of women reported non-smoking status early (51%) and late (53%) in pregnancy, confirmed by UDS. Using a traditional 8 ppm + cut-point for the early pregnancy reading, only 1% of non-smokers were incorrectly identified as smokers, but only 56% of all smokers, and 67% who smoked 5 + cigarettes in the previous 24 h, were identified. However, at 4 ppm +, only 8% of non-smokers were misclassified as smokers, and 90% of all smokers and 96% who smoked 5 + cigarettes in the previous 24 h were identified. False positives were explained by heavy second hand smoke exposure and marijuana use. Results were similar for late pregnancy ECO, with ROC analysis revealing an area under the curve of .95 for early pregnancy, and .94 for late pregnancy readings.

Conclusions

A lower 4 ppm ECO cut-point may be necessary to identify pregnant smokers using expired air samples, and this cut-point appears valid throughout pregnancy. Work is ongoing to validate findings in larger samples, but it appears if an appropriate cut-point is used, ECO is a valid method for determining smoking status in pregnancy.     

The effect of chronic exposure to 100 ppm carbon monoxide on brain biomines, serum corticosterone and organ weights in rats

The effect of chronic exposure to 100 ppm (0.01%) CO on pituitary-adrenal activity was evaluated by measuring serum corticosterone and brain bioamine levels in the rat. Exposure to CO for 1 month induced a decrease in the brain serotonin levels. Serum corticosterone, brain dopamine and noradrenaline as well as the weight of the adrenal glands, lungs, spleen and liver were unchanged. After two months of exposure, serum corticosterone and brain serotonin levels were elevated and the liver weight was significantly lower. This suggests that at this chronic low concentration CO acts as a stressor, and the organism initiates a general defensive reaction. The effect of CO on the pituitary-adrenal axis could be mediated by a central neuronal pathway.     

Timing and recovery of postweaning exposure to diethylstilbestrol on early pregnancy in CD-1 mice

Exposure timing could play an important role in the effects of estrogenic endocrine disrupting chemicals (EEDCs) on early pregnancy. This study examined the sensitivity of different exposure periods from weaning to gestation day 4.5 (D4.5) to 50 ppb diethylstilbestrol (DES, a test EEDC) diet on embryo implantation and potential recovery upon temporary cessation of DES exposure in CD-1 mice. Peripubertal (3–5 weeks old) DES exposure reduced the numbers of corpora lutea and implantation sites. Postpubertal (5–7 weeks old) DES exposure did not have significant effects on early pregnancy. Postmating (D0.5–D4.5) DES exposure affected postovulation events leading to impaired embryo implantation. A 5-day premating rest from 5-week DES exposure (3–8 weeks old) resulted in recovery of early pregnancy rate. These data demonstrate that peripubertal and postmating periods are sensitive windows to endocrine disruption of early pregnancy and temporary cessation of exposure could partially alleviate adverse effects of DES on early pregnancy.     

The effect of nicotine and total alkaloids extracted from cigarette smoke on avoidance behavior in rats under extinction procedure

The effect of nicotine and total alkaloids extracted from smoke on the avoidance behavior of rats under extinction procedure has been measured in an experiment extended over a period of three months. There was no significant difference between the two substances, with both inhibiting the extinction of avoidance response to approximately the same degree. Significance against the control was achieved with all treatments, the effect being significantly greater with the dose of 0.2 mg/kg than with the two doses of 0.1 or 0.05 mg/kg.This study was made possible through the help of a research grant from the Swiss Association of Cigarette Manufacturers.     

Long-term,low-level exposure of guinea pigs and marmosets to sarin vapor in air: lowest observable effect level

Realistic scenarios for low-level exposure to nerve agents will often involve exposures over several hours to extremely low doses of agent. In order to expose animals to the lowest controllable concentrations of agent and to increase exposure times until a lowest observable effect level (LOEL) becomes measurable, a validated system was developed for exposing conscious animals to 0.05-1.0 microg/m(3) (8-160 ppt) of sarin and other nerve agents. Based on cold trapping of sarin from the exposure air, the concentration could be measured semicontinuously, at 4-min time intervals by means of gas chromatography. We found that the LOEL upon a 5-h whole body exposure of guinea pigs and marmosets to sarin vapor corresponds with the measurement of an internal dose by means of fluoride-induced regeneration of sarin from phosphylated binding sites in plasma, mostly BuChE. For guinea pigs the LOEL was observed at Ct = 0.010 +/- 0.002 mg/min/m(3), whereas a Ct of 0.04 +/- 0.01 mg/min/m(3) was established for the LOEL in marmosets. These levels are several orders of magnitude lower than those based on classical measurement of depressed cholinesterase activities. At low exposure levels of guinea pigs and marmosets (< or =1 microg/m(3)), a reasonable linearity was observed between exposure dose and internal dose. The data were addressed in the light of the recently recommended occupational exposure limits to sarin for workers without respiratory protection, which suggests that the exposure limits should be reconsidered if the slightest inhibition of cholinesterases should be prevented.