Changes in levels of biomarkers of exposure and biological effect in a controlled study of smokers switched from conventional cigarettes to reduced-toxicant-prototype cigarettes.

BACKGROUND: Development of cigarettes that reduce exposure to harmful smoke constituents is a suggested tobacco harm reduction strategy, but robust methods for measurement of change are required. We investigated whether changes in biomarkers of exposure (BoE), effective dose (BoED) and biological effect (BoBE) could be detected after switching from conventional cigarettes to a reduced-toxicant-prototype cigarette (RTP). METHODS: Regular smokers of 6-8mg ISO tar yield cigarettes were recruited in Hamburg, Germany, and supplied with a conventional 7mg ISO tar yield cigarette for 2weeks then switched to the same cigarette with a different tipping paper (control) or the RTP for 6months. Subjects smoked mostly at home and attended five residential clinic visits where urine and blood samples were collected for analysis. Primary endpoints were changes in specific biomarker levels compared with non-smoker background levels. Changes in daily cigarette consumption were also investigated. RESULTS: BoE levels in controls generally increased over the study period, whereas most BoE and all BoED significantly declined in RTP smokers. Most BoBE data were similar across groups and/or too variable within individuals to detect changes. Increased daily cigarette consumption was affected by supply of free cigarettes, perceived shorter smoking time per cigarette than usual brands, and perceived reduced harm. CONCLUSIONS: Despite increased cigarette consumption, reductions in BoE and BoED were detectable.

Controlled exposure of humans with metabolic syndrome to concentrated ultrafine ambient particulate matter causes cardiovascular effects.

Many studies have reported associations between air pollution particles with an aerodynamic diameter <2.5 µm (fine particulate matter (PM)) and adverse cardiovascular effects. However, there is an increased concern that so-called ultrafine PM which comprises the smallest fraction of fine PM (aerodynamic diameter <0.1 µm) may be disproportionately toxic relative to the 0.1-2.5 µm fraction. Ultrafine PM is not routinely measured in state monitoring networks and is not homogenously dispersed throughout an airshed but rather located in hot spots such as near combustion sources (e.g., roads), making it difficult for epidemiology studies to associate exposure to ultrafine PM with adverse health effects. Thirty four middle-aged individuals with metabolic syndrome were exposed for 2 h while at rest in a randomized crossover design to clean air and concentrated ambient ultrafine particles (UCAPS) for 2 h. To further define potential risk, study individuals carrying the null allele for GSTM1 (a prominent antioxidant gene) were identified by genotyping. Blood was obtained immediately prior to exposure, and at 1 and 20 h afterward. Continuous Holter monitoring began immediately prior to exposure and continued for 24 h. Based on changes we observed in previous CAPS studies, we hypothesized that ultrafine CAPS would cause changes in markers of blood inflammation and fibrinolysis as well as changes in heart rate variability and cardiac repolarization. GSTM1 null individuals had altered cardiac repolarization as seen by a change in QRS complexity following exposure to UCAPS and both the entire study population as well as GSTM1 null individuals had increased QT duration. Blood plasminogen and thrombomodulin were decreased in the whole population following UCAPS exposure, whereas C-reactive protein (CRP) and SAA were increased. This controlled human exposure study is the first to show that ambient ultrafine particles can cause cardiovascular changes in people with metabolic syndrome, which affects nearly a quarter of the U.S. adult population.

A single-blinded, single-centre, controlled study in healthy adult smokers to identify the effects of a reduced toxicant prototype cigarette on biomarkers of exposure and of biological effect versus commercial cigarettes.

BACKGROUND: Despite universal acceptance that smoking is harmful, a substantial number of adults continue to smoke. The development of potential reduced exposure products (more recently termed modified risk tobacco products) has been suggested as a way to reduce the risks of tobacco smoking. This trial is designed to investigate whether changes in toxicant exposure after switching from a commercial to reduced toxicant prototype (RTP) cigarette (7 mg International Organisation for Standardisation (ISO) tar yield) can be assessed by measurement of biomarkers and other factors. The primary objective is to descriptively assess changes in selected biomarkers of exposure (BoE) and biomarkers of biological effect (BoBE) within participants and within and between groups after switching. Secondary objectives are to assess similarly changes in other biomarkers, quality of life, smoking behaviours, physiological measures, mouth-level exposure to toxicants and sensory perception. METHODS/DESIGN: This trial will assess current smokers, ex-smokers and never-smokers in a single-centre single-blind, controlled clinical trial with a forced-switching design and in-clinic (residential) and ambulatory (non-residential) periods. Smokers will be aged 23-55 years (minimum legal smoking age plus 5 years) and non-smokers 28-55 years (minimum legal smoking age plus 5 years, plus minimum 5 years since last smoked). Smokers will be allowed to smoke freely at all times. We will assess changes in selected BoE and BoBE and effective dose in urine and blood after switching. Creatinine concentrations in serum, creatinine clearance in urine, cotinine concentration in saliva, diaries and collection of spent cigarette filters will be used to assess compliance with the study protocol. Mouth-level exposure to toxins will be assessed by filter analysis. DISCUSSION: Data from this study are expected to improve scientific understanding of the effects of RTP cigarettes on BoE and BoBE, and give insights into study design for clinical assessment of potential MRTPs. TRIAL REGISTRATION: The study was registered in the Current Controlled Trials database under the reference ISRCTN81286286.

Association of cardiac and vascular changes with ambient PM2.5 in diabetic individuals.

BACKGROUND AND OBJECTIVE: Exposure to fine airborne particles (PM2.5) has been shown to be responsible for cardiovascular and hematological effects, especially in older people with cardiovascular disease. Some epidemiological studies suggest that individuals with diabetes may be a particularly susceptible population. This study examined effects of short-term exposures to ambient PM2.5 on markers of systemic inflammation, coagulation, autonomic control of heart rate, and repolarization in 22 adults (mean age: 61 years) with type 2 diabetes. METHODS: Each individual was studied for four consecutive days with daily assessments of plasma levels of blood markers. Cardiac rhythm and electrocardiographic parameters were examined at rest and with 24-hour ambulatory ECG monitors. PM2.5 and meteorological data were measured daily on the rooftop of the patient exam site. Data were analyzed with models adjusting for season, weekday, meteorology, and a random intercept. To identify susceptible subgroups, effect modification was analyzed by clinical characteristics associated with insulin resistance as well as with oxidative stress and by medication intake. RESULTS: Interleukin (IL)-6 and tumor necrosis factor alpha showed a significant increase with a lag of two days (percent change of mean level: 20.2% with 95%-confidence interval [6.4; 34.1] and 13.1% [1.9; 24.4], respectively) in association with an increase of 10 mug/m3 in PM2.5. Obese participants as well as individuals with elevated glycosylated hemoglobin, lower adiponectin, higher ferritin or with glutathione S-transferase M1 null genotype showed higher IL-6 effects. Changes in repolarization were found immediately as well as up to four days after exposure in individuals without treatment with a beta-adrenergic receptor blocker. CONCLUSIONS: Exposure to elevated levels of PM2.5 alters ventricular repolarization and thus may increase myocardial vulnerability to arrhythmias. Exposure to PM2.5 also increases systemic inflammation. Characteristics associated with insulin resistance or with oxidative stress were shown to enhance the association.