Institute For Science And Health

Tobacco Science and Health Program Initiative - Projects from RFA 2003-A

Dr. Derek Dunn-Rankin

Project Title: Size Segregated Chemical Composition of Tobacco Smoke Aerosol from Regular Cigarettes and Potentially Reduced Exposure Products (PREPs)

The Regents of the University of California, Irvine

Grant Award: $70,000
Duration: January 2005 - February 2006

Abstract:
The seed grant proposed will examine the variation in the chemical composition of mainstream smoke as a function of particle size distribution in order to estimate risk by cigarettes and Potentially Reduced Exposure Products (PREP), e.g. Advance lights. The work will utilize a research cigarette and a commercial cigarette for comparison with the PREP. The chemical constituents of smoke which are widely held to have major toxicological significance, like nicotine, NNK, NNN, NDEA, NDMA, B(a)P, benzo(h)fluroanthene, benzo(k)fluoranthene, and gaseous species like CO, NOx and CO2, will be employed as measuring species for this purpose. Mainstream smoke generated by the cigarettes will be collected through cascade impactors to obtain size-segregated samples of aerosol. These samples will be quantitatively analyzed for the abovementioned constituents using various chromatographic techniques (GC-TEA, GCMS, HPLC) and gas analyzers. To emulate the effect of various inhalation patterns by smokers, these chemical constituents will also be analyzed using different puffing regimens (FTC, long, short). The data pool generated will be statistically tested. The results will be analyzed to recognize chemical species whose particle size may play a role in determining aerosol behavior, e.g. deposition efficiency and location in the lung. It is important to recognize that cigarette smoke has important health associations with coronary disease as well as with cancer (Howard et al., 1998; Benowitz, 1997; Mullick et al., 2002; Shield, 2002). Though the mechanisms of coronary impact are not entirely clear, the role of gaseous species like carbon monoxide has been indicated (Smith and Fischer, 2001; Kayyali et al., 2003; Zevin et al., 2001; Seeman et al., 2002). Hence, in addition to condensed species, our project includes measurement of gas phase hydrocarbons, oxides of nitrogen, carbon monoxide, and carbon dioxide in order to help present a complete picture of the major contributors to the smoke mass. This project is a seed grant intended to demonstrate that measurements of cigarette smoke chemical composition as a function of particle size can be correlated to characteristics of cigarette construction and inhalation dynamics. With such a correlation, we will seek additional funding to create enough data to assist in evaluating potential health impacts from cigarettes and the new PREP products.

Priv.-Doz. Dr. Albrecht Seidel

Project Title: Biomonitoring of tobacco smoke-related aromatic amines in smokers versus non-smokers

Biochemical Institute for Environmental Carcinogens, Prof. Dr. Gernot Grimmer-Foundation

Grant Award: $221,000
Duration: April 2005 - March 2007

Abstract:
Several aromatic amines (AA) have been identified as bladder carcinogens in both experimental animals and humans. AA may account for the positive correlation between cigarette smoking and the incidence of bladder cancer in humans. However, only about 50% of attributed risk for bladder cancer is associated with cigarette smoking, which seems to indicate that there remains some exposure to AA that is not associated with tobacco smoke. Based on a comparative study of smokers vs. non-smokers the proposed project should allow (i) to identify potential sources of exposure of AA for non-smokers by means of questionnaire, (ii) to investigate the relationship between excreted AA levels in urine and hemoglobin(Hb) adduct levels, and (iii) to demonstrate a possible association between CYP1A2 phenotype, NAT1, NAT2 or GSTM1 genotypes and excreted AA levels in urine and Hb adduct levels in blood.

Dr. Kevin R. Smith

Project Title: Role of reactive oxygen species and cyclooxygenase-2 in tobacco smoke-induced inflammation and epithelial damage

The Regents of the University of California, Davis

Grant Award: $70,000
Duration: January 2005 - January 2006

Abstract:
A variety of animal models are used to study tobacco-induced COPD, but none demonstrate the full spectrum of expected changes including lung inflammation progressing from acute to chronic phases, mucous cell metaplasia, and air space enlargement. We have demonstrated exposure of the spontaneously hypertensive (SH) rat to tobacco smoke results in a striking degree of early pulmonary inflammation that persists throughout multiple weeks of exposure. This inflammation is accompanied by exuberant mucous cell hyperplasia. Further exposure to tobacco smoke in this model results in persistent epithelial airway hyperplasia and the genesis of alveolar distension within centriacinar locations of the lungs, reflective of centrilobular emphysema. Each feature is typical of changes in the lungs of human smokers with emphysema. The molecular mechanisms responsible for changes leading to COPD are as yet undetermined. However, reactive oxygen species, present in tobacco smoke, have been implicated in the pathogenesis of tobacco smoke-induced COPD. Reactive oxygen species are known to activate transcription factors, resulting in the synthesis of inflammatory mediators, such as prostaglandins which play a critical role in the initiation and progression of inflammation. We have shown repeated exposure of SH rats to tobacco smoke is associated with regulation of the inflammatory mediator cyclooxygenase-2 (COX-2). The use of the SH rat as a model of smoke induced pulmonary changes affords us the unique opportunity to elucidate more precisely those molecular, cellular, and pathological processes involved in smoke-induced lung disease. We will test the hypothesis that reactive oxygen species in TS induce over expression of COX-2 leading to elevated inflammation and remodeling of the airway epithelium. We hypothesize that these events can be blocked by antioxidants or inhibitors specific for COX-2. Changes will be measured using histopathologic, morphometric, and biochemical techniques.

Dr. Judith T. Zelikoff

Project Title: Prenatal exposure to cigarette smoke and chronic airway disease in the offspring: toxicological impact of the particulate and vapor phase

New York University School of Medicine

Grant Award: $397,221
Duration: February 2005 - January 2007

Abstract:

While the effects of gestational exposure to CS on childhood asthma is still being debated, accumulating epidemiologic and toxicologic data indicate that smoking during pregnancy increases the risk of airway hyperresponsiveness/respiratory impairment in the offspring. While the aforementioned findings are compelling and carry extensive clinical consequences, no data are available to provide insight into the particular smoke constituent(s) or possible mechanism(s) by which these effects may occur. Thus, a toxicological study is proposed to test the hypotheses that inhalation exposure to mainstream cigarette smoke (MS) - more specifically, its particulate phase - by pregnant mice influences airway reactivity in the offspring and, moreover, that these effects are gender-related and persistent. Using CD1 mice exposed daily (4 hr/d, 7 d/wk from gestational d 3 to parturition) to either mainstream CS minus the particulate phase (i.e., gas phase only [CS-]) or intact mainstream CS (CS+), the following two Specific Aims are proposed to: (1) assess the degree to which exposure of pregnant mice to each CS atmosphere, at a realistic concentration, modulates airway reactivity (as measured by non-specific [i.e., acetylcholine, Ach] bronchoprovocation challenge) in normal, unsensitized juvenile and adult male and female offspring; and (2) determine the effects of such exposures on the inducibility of allergen responses in cockroach antigen (CA)-sensitized offspring in response to specific bronchoprovocation stimuli (i.e., CA). For each of the above Aims, a dedicated subset of offspring will be used to ascertain whether (and the degree to which) biological parameters important in mediating airway reactivity (i.e., lavage cell profiles, levels of endogenous biological mediators, antigen-specific serum antibodies and, lung tissue-associated eosinophil and mast cell number 5) might be modified so as to determine more specifically some of the mechanisms by which CS (especially CS-associated particulates) might produce the observed outcomes. While it is recognized that the magnitude of the associated risk between CS exposure and airway dysfunction may be relatively low compared to other more dominant risk factors, given: that CS induced effects on lung function may continue throughout life; that smoking during pregnancy is a modifiable risk factor; the economic/emotional impact associated with airway disease; and that a better understanding of CS constituent toxicity can lead to development of a "smarter cigarette", assessment of the role of CS (and its individual components) in this regard is critical.