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Schramke H.,Philip Morris Products S.A. | Roemer E.,Philip Morris Products S.A. | Dempsey R.,Philip Morris Products S.A. | Hirter J.,Philip Morris Products S.A. | And 6 more authors.
Regulatory Toxicology and Pharmacology | Year: 2014

The biological activity of mainstream smoke from experimental kretek cigarettes with and without three mixes of ingredients was assessed in a 90-day rat inhalation study and in a 4-day in vivo micronucleus assay. 350 ingredients, commonly used in various combinations and in a limited number in a given brand in the manufacture of marketed kretek cigarettes, were applied at a low and a high target level to test cigarettes with a typical Indonesian blend of tobaccos and cloves. In the 90-day inhalation study, effects commonly seen in rat inhalation studies with mainstream smoke were observed. In general, no ingredients-related histopathological changes were found in the respiratory tract. In the 4-day micronucleus assay exposure of male rats to mainstream smoke from the test cigarettes containing any of the three mixes did not increase the proportions of micronucleated cells in peripheral blood and bone marrow over the proportion of micronucleated cells in the control group. Based on the results of these studies, it can be concluded that the addition of ingredients commonly used in the manufacture of kretek cigarettes did not change the overall in vivo toxicity profile of the mainstream smoke. © 2014 Elsevier Inc.

Piade J.-J.,Philip Morris Products S.A. | Roemer E.,Philip Morris Products S.A. | Dempsey R.,Philip Morris Products S.A. | Weiler H.,Philip Morris Research Laboratories GmbH | And 4 more authors.
Regulatory Toxicology and Pharmacology | Year: 2014

A typical Indonesian kretek cigarette brand and an experimental kretek reference cigarette were compared to the reference cigarette 2R4F in two 90-day inhalation studies. Male and female rats were exposed nose-only to mainstream smoke for 6 hours daily, for 90 consecutive days. Biological endpoints were assessed according to OECD guideline 413, with special emphasis on respiratory tract histopathology and on lung inflammation (broncho-alveolar lavage fluid levels of neutrophils, macrophages and lymphocytes). Histopathological alterations included: in the nose, hyperplasia and squamous metaplasia of the respiratory epithelium and squamous metaplasia and atrophy of the olfactory epithelium; in the larynx, epithelial squamous metaplasia and hyperplasia; in the lungs, accumulation of macrophages in alveoli and goblet cell hyperplasia in bronchial epithelium. The findings were qualitatively consistent with observations from previous similar studies on conventional cigarettes. Compared to 2R4F cigarette, however, kretek smoke exposure was associated with a pronounced attenuation of pulmonary inflammation and less severe histopathological changes in the respiratory tract. Neutrophilic inflammation was also significantly lower (>70%). These results are consistent with the observations made on smoke chemistry and in vitro toxicology. They do not support any increased toxicity of the smoke of kretek cigarettes compared to conventional American-blended cigarettes. © 2014 Elsevier Inc.

Roemer E.,Philip Morris Products S.A. | Dempsey R.,Philip Morris Products S.A. | Van Overveld F.J.,Philip Morris Research Laboratories bvba | Berges A.,Philip Morris Research Laboratories bvba | And 5 more authors.
Regulatory Toxicology and Pharmacology | Year: 2014

The biological effects of mainstream smoke (MS) from Indonesian-blended cigarettes with and without added cloves, cloves extracted with hot ethanol, and extracted cloves replenished with eugenol or clove oil were assessed in a 90-day inhalation study in rats. A separate 35-day inhalation study in rats was performed with MS from American-blended cigarettes with 0%, 2.5%, 5% or 10% added eugenol. Effects commonly seen in inhalation studies with MS were observed. These included histopathological changes indicative of irritation in the entire respiratory tract and inflammatory responses in the lung. Adding cloves to American- or Indonesian-blended cigarettes reduced the inflammatory response in the lung but with no difference between the two blend types. When the clove oil was extracted (~75% reduction of eugenol achieved) from cloves, the inflammatory response in the lung was still reduced similarly to whole cloves but the severity of histopathological changes in the upper respiratory tract was less reduced. Add back of clove oil or pure eugenol reduced this response to a level similar to what was seen with whole cloves. When eugenol was added to American-blended cigarettes, similar findings of reduced lung inflammation and severity of histopathological changes in respiratory the tract was confirmed. These studies demonstrate a clear effect of cloves, and in particular eugenol, in explaining these findings. © 2014 Elsevier Inc.

Meisgen T.,Philip Morris Research Laboratories GmbH | Roemer E.,Philip Morris Products S.A. | Conroy L.L.,Philip Morris Research Laboratories GmbH | Hostens J.,Philip Morris Research Laboratories bvba | And 5 more authors.
Beitrage zur Tabakforschung International/ Contributions to Tobacco Research | Year: 2014

Oxidative stress is a basic mechanism involved in both ageand smoking-related diseases. To test whether smoking affects young, old, and calorie-restricted organisms to the same extent, we assessed oxidative stress parameters in the lung, heart, and liver of male Fischer 344 rats (4 months old and 19-22 months old) exposed to air or cigarette mainstream smoke. Smoke-related effects were seen for parameters of DNA damage, lipid peroxidation, protein oxidation, and glycoxidation. No smoke-related effects were observed for DNA damage in the lung and heart (Comet assay) and for malondialdehyde in the lung. The old rats showed higher smoke-related responses than the young rats for 8-hydroxy-desoxyguanosine (8-OHdG) in the heart and liver, DNA damage in the liver, and protein carbonyls in the lung; however, there was little evidence for an overadditive effect of smoking on aging. Caloric restriction, which is known to retard aging effects, also had little impact on smoke-related oxidative changes. © 2014, Institut Fur Takforschung GMBH. All rights reserved.

Kogel U.,Philip Morris Research Laboratories GmbH | Kogel U.,Philip Morris Products S.A. | Schlage W.K.,Philip Morris Research Laboratories GmbH | Schlage W.K.,Philip Morris Products S.A. | And 15 more authors.
Food and Chemical Toxicology | Year: 2014

Towards a systems toxicology-based risk assessment, we investigated molecular perturbations accompanying histopathological changes in a 28-day rat inhalation study combining transcriptomics with classical histopathology. We demonstrated reduced biological activity of a prototypic modified risk tobacco product (pMRTP) compared with the reference research cigarette 3R4F. Rats were exposed to filtered air or to three concentrations of mainstream smoke (MS) from 3R4F, or to a high concentration of MS from a pMRTP. Histopathology revealed concentration-dependent changes in response to 3R4F that were irritative stress-related in nasal and bronchial epithelium, and inflammation-related in the lung parenchyma. For pMRTP, significant changes were seen in the nasal epithelium only. Transcriptomics data were obtained from nasal and bronchial epithelium and lung parenchyma. Concentration-dependent gene expression changes were observed following 3R4F exposure, with much smaller changes for pMRTP. A computational-modeling approach based on causal models of tissue-specific biological networks identified cell stress, inflammation, proliferation, and senescence as the most perturbed molecular mechanisms. These perturbations correlated with histopathological observations. Only weak perturbations were observed for pMRTP. In conclusion, a correlative evaluation of classical histopathology together with gene expression-based computational network models may facilitate a systems toxicology-based risk assessment, as shown for a pMRTP. © 2014 The Authors.

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