Peyton Jacob

Levels of selected carcinogens and toxicants in vapour from electronic cigarettes

Significance Electronic cigarettes, also known as e-cigarettes, are devices designed to imitate regular cigarettes and deliver nicotine via inhalation without combusting tobacco. They are purported to deliver nicotine without other toxicants and to be a safer alternative to regular cigarettes. However, little toxicity testing has been performed to evaluate the chemical nature of vapour generated from e–cigarettes. The aim of this study was to screen e-cigarette vapours for content of four groups of potentially toxic and carcinogenic compounds: carbonyls, volatile organic compounds, nitrosamines and heavy metals. Materials and methods Vapours were generated from 12 brands of e-cigarettes and the reference product, the medicinal nicotine inhaler, in controlled conditions using a modified smoking machine. The selected toxic compounds were extracted from vapours into a solid or liquid phase and analysed with chromatographic and spectroscopy methods. Results We found that the e-cigarette vapours contained some toxic substances. The levels of the toxicants were 9–450 times lower than in cigarette smoke and were, in many cases, comparable with trace amounts found in the reference product. Conclusions Our findings are consistent with the idea that substituting tobacco cigarettes with e-cigarettes may substantially reduce exposure to selected tobacco-specific toxicants. E-cigarettes as a harm reduction strategy among smokers unwilling to quit, warrants further study. (To view this abstract in Polish and German, please see the supplementary files online.)

Nicotine Chemistry, Metabolism, Kinetics and Biomarkers

Nicotine underlies tobacco addiction, influences tobacco use patterns, and is used as a pharmacological aid to smoking cessation. The absorption, distribution and disposition characteristics of nicotine from tobacco and medicinal products are reviewed. Nicotine is metabolized primarily by the liver enzymes CYP2A6, UDPglucuronosyltransferase (UGT), and flavin-containing monooxygenase (FMO). In addition to genetic factors, nicotine metabolism is influenced by diet and meals, age, sex, use of estrogen-containing hormone preparations, pregnancy and kidney disease, other medications, and smoking itself. Substantial racial/ethnic differences are observed in nicotine metabolism, which are likely influenced by both genetic and environmental factors. The most widely used biomarker of nicotine intake is cotinine, which may be measured in blood, urine, saliva, hair, or nails. The current optimal plasma cotinine cut-point to distinguish smokers from non-smokers in the general US population is 3 ng ml(-1). This cut-point is much lower than that established 20 years ago, reflecting less secondhand smoke exposure due to clear air policies and more light or occasional smoking.

Daily intake of nicotine during cigarette smoking

Daily intake of nicotine in 22 subjects was estimated from metabolic clearance data obtained after intravenous infusion of nicotine and from blood and urinary nicotine concentration data obtained over 24 hr when the subjects were smoking cigarettes. Daily intake of nicotine averaged 37.6 mg (±17.7, SD) but varied widely among subjects (10.5 to 78.6 mg). Men metabolized nicotine faster than did women, but daily intake of nicotine did not differ. Intake correlated strongly with cigarettes smoked per day (r = 0.59) but not with machine‐determined yield. Nicotine intake per cigarette averaged 1.04 mg (±0.36) but did not correlate with machine‐determined yield. Correlations between several commonly used biochemical markers of tobacco smoke and nicotine intake were examined; the afternoon (4:00 P.M.) blood level of nicotine was the best marker.

Cotinine disposition and effects

Cotinine is the major metabolite of nicotine in man. We studied cotinine disposition kinetics in 28 healthy habitual cigarette smokers. Eight subjects received cotinine fumarate, 4 μg base/kg/min IV for 60 min. Mean (±SD) metabolic clearance was 60 ± 12 ml/min and mean renal clearance was 12 ± 5 ml/min, averaging 17% of total clearance. Steady‐state volume of distribution was slightly greater than body weight (mean 88 ± 17 l). Terminal t½ averaged 15.8 ± 4.0 hr in these eight subjects and 19.7 ± 6.5 hr in another 12 subjects who abstained from smoking for 3 days. The effect of urinary acidification and alkalinization on renal clearance of cotinine during cigarette smoking was studied in another group of eight subjects. Compared with baseline (mean urinary pH 5.8, renal clearance 12.3 ± 5.9 ml/min), renal clearance was increased about 50% by urinary acidification (pH 4.4, clearance 18.6 ± 10 ml/min), but it was not affected by alkalinization (pH 6.7, clearance 14.0 ± 10.4 ml/min). Infusion of cotinine to blood concentrations seen in moderately heavy smokers had no effect on heart rate, blood pressure, or skin temperature, measures that are sensitive to effects of nicotine. No spontaneous subjective effects were reported. We conclude that, at levels to which cigarette smokers are generally exposed, cotinine exerts no cardiovascular activity and weak, if any, psychologic activity.

Disposition kinetics and effects of intravenous nicotine.

Nicotine was given intravenously to subjects during acid and alkaline urine conditions in doses and a dosing schedule designed to simulate cigarette smoking. Total clearances were greater, terminal half‐lifes shorter, but volumes of distribution much the same in acid (pH < 5) and alkaline (pH > 7) urine conditions. The effect of urinary pH on total clearance was due entirely to changes in renal clearance, which accounted for 23% and 2% of total clearance in acid and alkaline urine conditions. Nicotine injections induced a sensation of arousal and increased heart rate and blood pressure over the short term, but with repeated injections tolerance to these effects developed rapidly. No differences in subjective or physiologic responses to intravenous nicotine were observed and we consider it unlikely that the effects of smoking a cigarette differ as a function of urinary pH.

Nicotine intake and dose response when smoking reduced–nicotine content cigarettes

The progressive reduction of the nicotine content of cigarettes has been suggested as a way to wean smokers from nicotine and tobacco. As a first step in evaluating this strategy, we studied smokers smoking cigarettes containing tobacco with differing nicotine content.

Short-term metabolic and hemodynamic effects of ephedra and guarana combinations.

Serious adverse health events have been reported with the use of dietary supplements containing ephedra and guarana. We sought to determine whether repeated dosing and multi‐ingredient formulations contribute to the adverse effects of these supplements.

Presystemic metabolism of meperidine to normeperidine in normal and cirrhotic subjects

Plasma concentrations and urinary excretion of meperidine and its metabolite normeperidine were determined after intravenous and oral administration to 11 men; five men had hepatic cirrohosis and six were normal. Systemic clearance of meperidine was smaller and bioavailability and half‐life greater in the cirrhotic patients than in the normal subjects. Plasma concentrations and 24‐hr urinary excretion of normeperidine was lower and persistence of normeperidine in plasma longer in the patients with cirrhosis. The route of administration did not alter the fraction of normeperidine generated from meperidine. The results suggest that in patients requiring repeated meperidine dosage the drug should be taken parenterally rather than orally to allow maximal analgesia and minimal formation of normeperidine. Patients with cirrhosis may be relatively protected from normeperidine toxicity because of impaired formation, but the risk of cumulative toxicity may be greater than in normal subjects because of slower elimination of the metabolite and greater sensitivity to the effects of narcotics on the central nervous system.

Lack of effect of diazepam on methadone metabolism in methadone‐maintained addicts

Four methadone‐maintained subjects were given diazepam (0.3 mg/kg) for 9 days. During the dual drug period, the effects and kinetics of methadone and of its major pyrrolidine metabolite were not altered. These findings indicate that, unlike its effects in rodents, diazepam does not inhibit the metabolism of methadone in man.

Racial differences in the relationship between tobacco dependence and nicotine and carcinogen exposure

AIMS To investigate the relationships between tobacco dependence, biomarkers of nicotine and carcinogen exposure and biomarkers of nicotine and carcinogen exposure per cigarette in back and white smokers. DESIGN, SETTING AND PARTICIPANTS A total of 204 healthy black (n = 69) and white (n = 135) smokers were enrolled into two clinical studies. MEASUREMENT Nicotine equivalents (nicotine and its metabolites), 4-(methylnitrosamino)-1-(3)pyridyl-1-butanol (NNAL) and polycyclic aromatic hydrocarbon (PAH) metabolites were measured in urine. The Fagerström Test for Nicotine Dependence (FTND) and time to first cigarette (TFC) measured tobacco dependence. FINDINGS Average TFC and FTND for blacks and whites were not significantly different. Urine NNAL and nicotine equivalents increased with increasing FTND in whites but did not increase in blacks (race × FTND interaction, both P < 0.031). The interaction term was not significant for PAHs. An inverse relationship was seen between FTND and nicotine equivalents, NNAL and PAH metabolites per cigarette in blacks but remained flat in whites (race × FTND interaction, all P ≤ 0.039). Regardless of dependence (low dependence, TFC >15 minutes; high dependence, TFC ≤15 minutes), FTND and TFC were not correlated significantly with urine nicotine equivalents and carcinogen exposure in blacks. We found moderate correlations between FTND and TFC and nicotine equivalents and carcinogen exposure among whites of low dependence and non-significant correlations among whites of high dependence. CONCLUSION In the United States, tobacco dependence measures were related linearly to nicotine intake and carcinogen exposure in white but not in black smokers. The relationship between dependence measures and tobacco biomarkers in black smokers regardless of level of dependence resembled highly dependent white smokers.