Toxicological assessment of kretek cigarettes part 3: Kretek and American-blended cigarettes, inhalation toxicity

Abstract

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.

Toxicological assessment of kretek cigarettes part 5: Mechanistic investigations, inhalation toxicity

“…Accordingly, the eugenol content does not appear to fully explain the reduced inflammatory potential found with kretek cigarettes. Overall, these findings closely resemble what was observed in the 90-day inhalation study of Garam relative to 2R4F (Piadé et al, 2014b) and confirm an important role of eugenol.…”

“…Histopathological observations (hyperplasia, metaplasia, and atrophy) were qualitatively similar to previous inhalation studies of mainstream cigarette smoke from American-blended cigarettes and with the comparative assessment of the reference cigarette 2R4F, Garam, and the Kretek-R cigarette in this publication series (Piadé et al, 2014b). Smoke-exposed male rats showed a response in most histopathological endpoints relative to sham but there was no statistically significant difference in severity between the cigarette groups at the end of the 90-day inhalation period.…”

Cigarette smoke induced genotoxicity and respiratory tract pathology: evidence to support reduced exposure time and animal numbers in tobacco product testing

“…Many CS exposure studies in the rat have detailed that histopathological responses do not occur in non-respiratory tract organs (Baker et al, 2004 ; Fujimoto et al, 2015 ; Kogel et al, 2014 ). An exception, however, is a slight increase in thymus atrophy observed in CS-exposed animals (Piade et al, 2014 ; Roemer et al, 2014 ), which is postulated to occur due to smoke irritation and stress induced by restraint during exposure (Gruver & Sempowski, 2008 ). Indeed, those two studies used 6, rather than 1, h of exposure/day, which might have increased the level of stress.…”

“…The Organization for Economic Co-operation and Development (OECD) Guideline 413 (OECD, 2009 ), a rodent nose-only sub-chronic inhalation toxicity guideline, can be used with minor modifications to test both cigarettes (Gaworski et al, 2009 ; Schramke et al, 2014 ) and products that heat tobacco (Fujimoto et al, 2015 ). The OECD 413 protocol stipulates that inhalation should be for 90 days, however, CS induced pathology can be identified within the rat respiratory tract prior to 90 days (Fujimoto et al, 2015 ; Kogel et al, 2014 ; Piade et al, 2014 ; Walker et al, 1978a,b ). Numerous studies have detailed the characteristic histopathological respiratory tract lesions that develop following long-term CS exposure (Baker et al, 2004 ; Gaworski et al, 2009 ; Potts et al, 2007 ; Werley et al, 2013 ).…”

Tobacco Products

“…Yoğun karanfil tadı ve kokusuna ek olarak, her kretek markasının tadını belirleyen ve sır gibi saklanan özel bir sosu bulunmaktadır. Endonezya'da sigara piyasasında %93'lük pay ile ilk sırada kretek yer almaktadır (14) .Yapılan ça-lışmalarda kretek normal sigaralardan daha zararlı olarak bildirilmemiştir (15)(16)(17)(18) . Pipo: Pipo, tütün tarihinin en eskilerindendir.…”