Could charcoal filtration of cigarette smoke reduce smoking-induced disease? A review of the literature

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Regulatory Toxicology and Pharmacology 50 (2008) 359–365 www.elsevier.com/locate/yrtph

Could charcoal filtration of cigarette smoke reduce smoking-induced disease? A review of the literature Christopher R.E. Coggins a,1, Charles L. Gaworski b,* b

a Carson Watts Consulting, King, NC 27021, USA Philip Morris USA, PO Box 26603, Richmond, VA 23261, USA

Received 18 October 2007 Available online 16 January 2008

Abstract A review of the published work with charcoal-filtered cigarettes indicates that there are reductions in the concentrations for many gasvapor phase constituents found in mainstream smoke. However, charcoal filters provided no apparent capacity for reduction of smoke particulate phase components. The reductions in gas–vapor phase smoke chemistry analytes generally correspond with findings of reduced toxicological activity, principally related to a reduction in the cytotoxic action of the volatile smoke constituents. Results of a short-term clinical study show small reductions in the biomarkers of the gas–vapor phase smoke constituents in subjects smoking charcoal-filtered cigarettes, compared to subjects smoking non-charcoal filtered cigarettes. The very limited epidemiology data (a single study) fail to demonstrate a conclusive beneficial effect of charcoal-filtered cigarette products compared to non-charcoal filtered cigarette products. Review of the scientific literature is hindered due to the lack of documentation regarding the activity of the charcoal used in the filter, and the inconsistency in product designs used between the various different disciplines (chemistry, pre-clinical, clinical and epidemiology) that have conducted studies with charcoal filtered cigarettes. There do not appear to be any published studies using a combination of data from the different disciplines based on a consistently designed charcoal cigarette filter. Although the literature presently available would suggest that smoke filtration provided by current charcoal filter techniques alone may not be substantial enough to reduce smoking-related disease, the data are limited. Therefore, for the reduction of smoking-induced disease, it is difficult to come to a definitive conclusion regarding the potential health benefits of using charcoal as a smoke filtration technology. Ó 2008 Elsevier Inc. All rights reserved. Keywords: Charcoal; Carbon; Filtered cigarettes

1. Introduction This document is an analysis of published work on the use of charcoal or ‘‘carbon” filters on cigarettes, filters that are considered to be effective in reducing gas–vapor phase components of mainstream cigarette smoke (Morie et al. 1975; Baggett and Morie 1975). Charcoal filters are currently popular in such localized geographical areas as Hungary, Japan, Switzerland, South Korea, and Venezuela *

Corresponding author. Fax: +1 804 274 3491. E-mail address: [email protected] (C.L. Gaworski). 1 Dr. Coggins is a consultant to Philip Morris USA Inc., and as such received payment for his contribution to the manuscript. 0273-2300/$ - see front matter Ó 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.yrtph.2008.01.001

(Fisher 2000), but in the USA the popularity of such filters is very low. It has been suggested that there should be mandatory incorporation of such filters, and protagonists of this idea ‘‘estimated that an effective charcoal filter could reduce a brand’s overall relative toxicity score for identifiable toxicant by over 40%” (Laugesen and Fowles 2005). On the other hand, others (Pauly et al. 1997) have cautioned that charcoal filters may actually increase the toxicological profile of cigarettes by releasing carbon particles laden with PAHs. Such a suggestion seems unlikely, however, based on studies of transfer efficiencies (Agyei-Aye et al. 2004). Other work (Laugesen and Fowles 2006) has suggested that charcoal filtration may not result in significant reductions in toxicological profiles of commercial cigarettes to the

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extent of resulting in a ‘‘Potentially Reduced Exposure Product” (Institute of Medicine 2001). 2. Results 2.1. Mainstream smoke chemistry An elegant study (Xue et al. 2002) with modified 1R4F reference cigarettes (Diana and Vaught 1990) showed that ‘‘activated carbon shows very high removing activity for all of the gas phase components measured except carbon dioxide and ethane”. In this work, the 1R4F cigarettes were modified by placing the adsorbent in a plug/space/plug filter configuration (a ‘‘triple filter”). The authors wrote that this was done to reduce apparent contamination of activated charcoal by the use of the cross-linking agent triacetin in the plug-making process (Norman 1999), which ‘‘results in lower filtration activity for smoke gas-phase components” (Xue et al. 2002). Table 2 of that paper shows the percentage reductions in 24 of 26 gas phase components when the 1R4F University of Kentucky reference cigarettes were fitted with the special filter, compared with no such modification: in virtually all cases these reductions were around 90%. The authors considered that these reductions by activated carbon were ‘‘due to its high surface area and diversified surface activity” (Xue et al. 2002). 2.2. Pre-clinical studies: in vitro Genetic effects of cigarette smoke were examined using whole smoke exposures of yeast cells (Saccharomyces cerevisiae) and in a modification of the Salmonella test. In addition, total particulate matter (TPM) extracts from Cambridge pads were obtained and applied to strain TA98 bacteria, with S9 metabolic activation in the conventional Salmonella mutagenesis assay (Gairola 1982). A variety of different commercial and reference cigarettes (including ‘‘lettuce cigarettes”) were used and responses were compared with the response produced by the unfiltered 2R1 reference cigarette. Filtration effects were studied by placing charcoal (25, 50, 100 or 200 mg) or Cambridge filters in the smoke path, directly behind the cigarette. Smoke was then passed to the in vitro culture exposure system (Gairola 1982). Cigarette smoke produced ‘‘an increase in the frequency of all of the genetic endpoints examined in this study”, in general with a dose response. The addition of charcoal reduced the activity significantly, again, with a dose response (Gairola 1982). The author concluded that ‘‘activated charcoal, at commercially feasible levels, was very effective in reducing [genetic] activity in proportion to the quantity of charcoal used” (Gairola 1982). Although many charcoal filters have a triple filter configuration, others use charcoal incorporated into a paper matrix (Norman 1999). This latter format has been shown to reduce ‘‘carbonyls such as formaldehyde, acetaldehyde, and acrolein from mainstream cigarette smoke to a signifi-

cant degree” (Bombick et al. 1997). Evaluations of such a filter were made using several in vitro indicators of genotoxic and cytotoxic potential, of both whole smoke and of the particulate phase of the whole smoke of experimental cigarettes. The tests used were the Salmonella mutagenicity assay (using only the TA98 strain, with S9, for TPM only), sister chromatid exchange in Chinese hamster ovary (CHO) cells, and the neutral red cytotoxity assay, also in CHO cells. The charcoal filter did not affect the genotoxic or cytotoxic effects of the TPM. However, when whole smoke was evaluated there were ‘‘significant reductions in genotoxic and cytotoxic potential compared to cigarettes without the novel carbon filter” (Bombick et al. 1997). There were correlations between the toxicity of the smoke and the ‘‘aggregate mass of several vapor phase components”. The authors concluded that ‘‘reductions of vapor-phase components by the new carbon filter are responsible for the reduced cytotoxicity and genotoxicity of the whole smoke” (Bombick et al. 1997). Cultures of hamster lung cells were exposed for 3 days to smoke that had been passed through activated coconutshell charcoal (Leuchtenberger et al. 1974). One of the endpoints studied was the ‘‘sulfhydryl (SH) index”: the percentage of cysteine consumed by the smoke of 60 cigarettes. Analyses of smoke from cigarettes with a charcoal filter showed ‘‘a striking reduction of the gas vapour phase constituents and of the SH index, whereas the content of nicotine and total particulate matter closely resembled that of the smoke from cigarettes without a charcoal filter”. The results obtained showed that ‘‘exposure of reduced gas vapour phase constituents and low SH reactivity not only produces less damage to the cells, but also less abnormal growth and disturbance of DNA complement in the chromosomes than smoke with higher vapour phase constituents and a higher SH reactivity” (Leuchtenberger et al. 1974). A further study from the same group as the one described above used very similar techniques, but with much longer exposures of the hamster lung cell cultures, up to 37 weeks (Davies et al. 1975). Additional cultures were injected subcutaneously into nude mice and the tumors formed were examined by electron microscopy. The results were ‘‘in accordance with those previously obtained, which suggested that in smoke-exposed primary cultures of hamster lung cells, the gas vapour phase of cigarettes contributes appreciably to promoting those changes which accompany oncogenicity”. However, the results suggested that ‘‘after exposure to cigarette smoke low in gas vapour phase constituents, the cell cultures display features similar to those of controls of the same age” (Davies et al. 1975). 2.3. Pre-clinical studies: ex vivo The effect of cigarette smoke on ciliary transport was studied in several different species, using tracer particles (‘‘finely powdered soot and lycopodium spores”) in excised

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tracheas (Kensler and Battista 1963). It was thought that ciliastasis and impaired clearance of materials from the lung could be one of the mechanisms involved in smoking-induced disease. These studies used diluted cigarette smoke from seven commercial brands of cigarettes, including one with ‘‘a filter that contained a filter section of paper impregnated with carbon as well as a section of cellulose acetate”. Two of the seven cigarette brands were unfiltered. Individual gases (hydrogen cyanide, formaldehyde, acetaldehyde, acrolein, nitrogen dioxide) were also used. The authors found that cigarette smoke had considerable ciliary-depressant activity, and this activity ‘‘resides in the gas phase rather than the particulate phase”. The charcoal-granule filter was ‘‘found to reduce the ciliaryinhibitory activity of cigarette smoke for tracheal preparations from dogs, cats and monkeys”. Among the various components of the gas phase, ‘‘hydrogen cyanide, ammonia, formaldehyde, acrolein and nitrogen dioxide were found to have appreciable ciliary-depressant activity” (Kensler and Battista 1963). Among the conclusions made, the authors considered that ‘‘it is recognized that these in vitro findings may not be directly extrapolated to the effects of cigarette smoke on human pulmonary tissue.” Any long-term reduction in smoke-induced ciliastasis would presumably be beneficial (see below). 2.4. Pre-clinical studies: in vivo A study published in German used mouse skin painting with cigarette smoke condensate to evaluate a charcoalimpregnated filter (up to 380 mg per filter) (Dontenwill et al. 1970). The English abstract states that ‘‘Experimentally observed differences between the effect of the condensate from cigarettes with charcoal filters and of standard condensate is statistically not significant”. A similar cigarette as in the above study, with up to 340 mg pressed charcoal (‘‘Tempo”) from coconut shell carbon, was used in a complicated inhalation study with Syrian golden hamsters (Dontenwill et al. 1974). Additional details were that ‘‘the charcoal had a grain size of 0.5– 1.5 mm, with an active surface area of >1000 m2, and with a pressure drop of 45 mm water”. The responses were evaluated after twice-daily inhalation exposures for the lifetime of the animals: approximately 1 year. Most of the resulting pathological changes occurred in the larynx. The only finding mentioned for the charcoal filter group was that a reduction in biological activity ‘‘was less in hamsters exposed to the cigarette with the charcoal filter”. The ‘‘reductions in biological activity” referred to lower severity scores for laryngeal leukoplakia, reductions that were noted for ‘‘black cigarettes, cigarettes with cellulose filters, and cigarettes with cellulose acetate filters”, but not for the charcoal filter cigarettes (Dontenwill et al. 1974). A similar type of charcoal filter was used in a comparison of the effects in rats of exposure to the particulate and vapor phases of mainstream smoke (Coggins et al. 1980). Here, the charcoal filter on the cigarettes was 25 mm long,

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consisting of 360 mg of carbon granules bonded onto polyethylene (15 mm) and cellulose acetate (10 mm), and the resultant exposure was considered to be to ‘‘particulate phase only”. Results were compared with those obtained using filtration of the particulates of the smoke (‘‘Cambridge filters”), considered to result in exposures to ‘‘vapor phase only”. Cigarettes contained flue-cured tobacco only. A number of pathological changes were presented, concentrating largely upon laryngeal responses, but extensive deciliation was also observed at the tracheal bifurcation (carina). The authors concluded that ‘‘none of the above changes could be directly attributed to exposure to vapour phase alone, and in many cases the lesions produced by whole smoke and by carbon filtered smoke were directly comparable” (Coggins et al. 1980). Investigations of ciliary-depressant activity lead to the observation that ‘‘for lesions to occur in some ciliated areas of the [upper respiratory] tract both phases of the smoke were required”. Using a similar experimental design as the one described above, this same group using whole-body plethysmography demonstrated that the reduction in minute ventilation of smoke-exposed rats was due to components of the vapor phase of the whole smoke (Coggins and Ventrone 1986). Ciliastasis was also examined in a study with Syriangolden hamsters, using weekly intratracheal instillations of benzo[a]pyrene (‘‘B(a)P”) (Zeller and Schma¨hl 1986). The animals were also exposed for up to 73 weeks to ‘‘inhalation of cigarette smoke, with and without filtration by carbon filters.” In one experiment activated charcoal was placed in the smoke stream between the cigarettes and the animals; in a second experiment some of the cigarettes had carbon-containing acetate filters. In both experiments the ‘‘yield of pathologic changes in the bronchial system following smoke-inhalation with B(a)P instillation was reduced by 40–50% in those groups in which the smoke stream passed through an additional carbon filter compared to the respective groups without carbon filter” (Zeller and Schma¨hl 1986). The cautious interpretation of these results by the authors was that ‘‘carbon filters have a protective effect and apparently can delay or reduce formation of experimental bronchogenic carcinomas”. Similar protective responses of charcoal filtration were obtained in acute exposures of rats to filtered smoke (Lam 1980), even though this study used only a single hour of exposure. The only endpoint in this study was partial or complete loss of the epithelium on the ventral surface of the larynx, accompanied by acute inflammation, edema, and the presence of debris in the laryngeal lumen. This work used four different cigarette types, including one with a bonded carbon filter. Rats were exposed to smoke at different nominal dilutions and were killed at different time intervals after the end of the single hour of exposure. There was also (as above) a group exposed to vapor phase only, produced by placing a Cambridge pad in the smoke path. The author found that ‘‘virtually all of the laryngeal damage caused by acute smoke exposure was due to the particulate phase of the smoke”. However, carbon

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filtration at comparable smoke TPM concentrations produced higher mean scores than did the cigarettes without the filter. The author considered that this increase may have been due to a selective removal of semi-volatile components of smoke by the carbon filter. Vapor phase alone produced no changes. 2.5. Clinical trial In a randomized, crossover, 2-week brand-switching study with 39 smokers (Scherer et al. 2006) twenty of the subjects smoked cellulose acetate (CA) filter tipped cigarettes during week 1 of the study; the remaining 19 subjects smoked charcoal (CC) filter tipped cigarettes during week 1. In week 2, the subjects switched to the corresponding brand with the other filter type, with similar smoking machine-derived tar and nicotine yields. No other smoke chemistry was presented. The study was probably of much too short a duration for smokers to fully adjust to the new cigarette design characteristics. Longer-term exposures would be required to detect changes in smoking behavior related to the switch to a different cigarette (Roethig et al. 2005), particularly one with such a markedly different organoleptic profile. Daily cigarette consumption, carbon monoxide in exhaled breath, salivary cotinine, and urinary nicotine equivalents (molar sum of nicotine plus five major metabolites) did not change significantly when switching to the cigarettes with the other filter type. Urinary excretion rates of 3-hydroxy-1-methylpropylmercapturic acid (metabolite of crotonaldehyde), monohydroxybutenylmercapturic acid (metabolite of 1,3-butadiene), and S-phenylmercapturic acid (metabolite of benzene) were significantly lower when smoking CC compared to CA filter tipped cigarettes. The reduction in amount of 3-hydroxypropylmercapturic acid (metabolite of acrolein) was of borderline significance. Other mercapturic acids and thioethers were not or were only slightly reduced upon smoking CC filter tipped cigarettes (Scherer et al. 2006). The authors concluded that ‘‘smoking CC filter tipped cigarettes does not change the uptake of carbon monoxide and nicotine when compared to CA filter tipped cigarettes with similar tar and nicotine yields, but significantly reduces the exposure to toxicologically relevant smoke constituents such as acrolein, crotonaldehyde, 1,3-butadiene, and benzene” (Scherer et al. 2006). 2.6. Epidemiology As mentioned above, charcoal filters are very popular in cigarettes sold in Japan. To estimate smoking-specific relative risks for lung cancer in men, a multi-center case-control study was carried out in New York City, Washington, DC, and Nagoya, Japan from 1992 to 1998 (Stellman et al. 2001). A total of 371 cases and 373 agematched controls were interviewed in United States hospitals and 410 cases and 252 hospital controls in Japanese

hospitals; 411 Japanese age-matched healthy controls were also randomly selected from electoral rolls. The odds ratio (OR) for lung cancer in current U.S. smokers relative to nonsmokers (adjusted for a number of confounding variables) was 40.4 (95% confidence interval, or CI = 21.8– 79.6), which was >10 times higher than the OR of 3.5 for current smokers in Japanese relative to hospital controls (CI = 1.6–7.5) and six times higher than in Japanese relative to community controls (OR = 6.3; CI = 3.7–10.9). There were no substantial differences in the mean number of years of smoking or average daily number of cigarettes smoked between U.S. and Japanese cases or between U.S. and Japanese controls, but American cases began smoking on average 2.5 years earlier than Japanese cases (Stellman et al. 2001). Also, the Japanese data are for adenocarcinoma only, whereas the U.S. data are for adenocarcinoma and for small cell carcinoma. The risk of lung cancer associated with cigarette smoking in males was substantially higher in U.S. than in Japanese males, ‘‘consistent with population-based statistics on smoking prevalence and lung cancer incidence”. To the authors, possible explanations for this difference in risk included ‘‘a more toxic cigarette formulation of American manufactured cigarettes as evidenced by higher concentrations of tobacco-specific nitrosamines in both tobacco and mainstream smoke, the much wider use of activated charcoal in the filters of Japanese than in American cigarettes, as well as documented differences in genetic susceptibility and lifestyle factors other than smoking” (Stellman et al. 2001). In addition, Muscat and co-workers (Muscat et al. 2005) hypothesized that the apparently lower lung cancer mortality rate in Japan than in the U.S. is due to the Japanese preference for cigarettes with charcoal-containing filters, which ‘‘efficiently absorb selected gas phase components of mainstream smoke including the carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone”, NNK (Muscat et al. 2005). The authors analyzed a subset of smokers (396 cases and 545 controls) from a case-control study of lung cancer conducted in Aichi Prefecture, Japan. The risk associated with charcoal filters (73% of all subjects) was evaluated after adjusting for age, sex, education and smoking dose. No description is given of the way charcoal was incorporated into the filters, nor were any analyses of smoke chemistry made. The comment made above on possible lower charcoal-filtration activity due to the cellulose acetate cross-linking agent triacetin thus could be quite important here (Xue et al. 2002; Norman 1999). The OR associated with charcoal, compared with noncharcoal, cigarette filters was 1.2 with a CI of 0.9–1.6, so the result is not considered to be statistically significant. The histologic-specific risks were similar (e.g. OR = 1.3, CI 0.9–2.1 for adenocarcinoma). The OR was 1.7 (CI 1.1–2.9) in smokers who switched from non-charcoal to charcoal brands. The mean daily number of cigarettes smoked in subjects who switched from non-charcoal to charcoal brands was 22.5 and 23.0, respectively.

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The authors concluded that their findings ‘‘did not indicate that charcoal filters were associated with an attenuated risk of lung cancer” (Muscat et al. 2005). They also suggested that ‘‘as the detection of a modest benefit or risk (e.g. 10–20%) that can have significant public health impact requires large samples, the findings should be confirmed or refuted in larger studies”. We agree that this single study may not have been sufficiently ‘‘powered” to demonstrate any beneficial effect of charcoal filtration, and that additional epidemiology studies are needed. The most recent paper examining Japanese and U.S. smokers (Wakai et al. 2006) compared several published studies; a meta-analysis was also conducted to estimate the summary measure of those associations. This work did not examine the use of charcoal filtration, but it is relevant to the ‘‘Japanese paradox” mentioned above. A total of eight cohort studies and 14 case-control studies were identified, almost all of which consistently showed a strong association of current smoking with the risk of lung cancer. The summary OR for current smokers versus never smokers was estimated as 4.39 (CI 3.92–4.92) for men and 2.79 (CI 2.44–3.20) for women. Cohort studies and case-control studies gave reasonably consistent summary measures. The summary ORs were 11.7 and 2.30 for squamous cell carcinoma and adenocarcinoma, respectively, in men, and were 11.3 and 1.37 correspondingly in women. The authors concluded that ‘‘there is convincing evidence that tobacco smoking strongly increases the risk of lung cancer in the Japanese population, with the relative risk for current smokers compared with never smokers measuring around 4.4 for men and 2.8 for women” (Wakai et al. 2006). The authors also considered a number of factors for the lower ORs in Japan (Sobue et al. 2002; Marugame et al. 2005), considering that the difference may be due to attributes unique to the Japanese smoker and non-smoker. The lower ORs in Japan may be ‘‘attributable to both the lower risk of lung cancer in current smokers and the higher risk in non-smokers” (Wakai et al. 2006), both of which determine the OR for smoking-induced lung cancer (compared with never smokers). 3. Discussion In a monograph on tobacco smoke and involuntary smoking (IARC 2004), the International Agency for Research on Cancer (IARC) indicated that tobacco smoke causes more cancer deaths than can be attributed to all other known causes in addition to causing deaths from vascular and respiratory disease. The Institute of Medicine concluded that for many diseases attributable to tobacco smoke, reducing the risk of disease by reducing exposure to tobacco toxicants is feasible (Institute of Medicine 2001). Nevertheless, there do not appear to be studies in humans smoking charcoal-filtered cigarettes where the endpoints were chronic obstructive pulmonary disease or cardiovascular disease, an important omission that urgently needs to be addressed.

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Cigarette smoke is a complex mixture of thousands of individual chemical constituents (Baker 1999) residing in a dynamic semi-liquid aerosol comprising 3–5  109 particles/cm3 with a mass median aerodynamic diameter range of 0.1–0.3 lm (Robinson and Yu 1999). In a report prepared for the New Zealand Ministry of Health analyzing priorities for harm reduction, several volatile carcinogenic chemicals such as 1,3-butadiene, acrylonitrile, arsenic, acetaldehyde and benzene were identified by a toxicological risk assessment method as having the highest cancer risk indices for individual chemicals of cigarette smoke (Fowles and Dybing 2003). One potential strategy for volatile toxicant exposure reduction is through the use of highly activated carbon in the cigarette filter. While charcoal-filtered cigarettes are not new to the cigarette market, they comprise only a small market share in the US (Fisher 2000), possibly for organoleptic reasons. In contrast, charcoal-filtered cigarettes are very popular in Asian countries such as Japan, where they comprise more than two-thirds of the market compared to <1% of the US market. These cigarettes generally contain relatively small amounts of charcoal, restricted in a filter cavity, incorporated in the filter material, or bonded to a paper surface (Norman 1999). Notable among the smoke constituents reduced by charcoal are chemicals such as 1,3-butadiene, acrylonitrile, acetaldehyde, benzene, cadmium and acrolein, and to a lesser extent, formaldehyde and 2-nitropropane. A review of ‘‘IARC Group I carcinogens” in smoke (Smith et al. 1997) considered that the ‘‘use of enhanced charcoal filters . . . would be expected to reduce the yields of several of these agents”. While 1,3-butadiene has not been shown to be a lung carcinogen in occupational settings, chronic exposures of mice to low levels of 1,3-butadiene have resulted in lung tumors. The link of such studies to humans was the subject of a recent review (Hurst 2007). Cockerels exposed to 1,3butadiene have demonstrated enhanced atherosclerotic plaque development (Penn and Snyder 1996a,b). A review (Korte et al. 2000) of the contribution of benzene to smoking-induced leukemia stated that ‘‘cigarette smoking is associated with an increased risk of leukemia; benzene, an established leukemogen, is present in cigarette smoke.” Tobacco is a major source of exposure to cadmium (IARC 2004), the latter having a probable role in lung cancer (Cox 2006). Formaldehyde and acetaldehyde are respiratory carcinogens in rodents (Woutersen et al. 1986; Woutersen et al. 1989), with formaldehyde now considered a human carcinogen (IARC 2004). Acrolein was recently suggested as ‘‘a major etiological agent for cigarette smoke-related lung cancer and that it contributes to lung carcinogenesis through two detrimental effects: DNA damage and inhibition of DNA repair” (Feng et al. 2006). Any reduction in potential exposure to compounds such as acrolein could therefore be highly beneficial as a component of strategies to reduce the risk of cigarette smoking. While charcoal filters have the potential for reducing exposure to certain mainstream smoke constituents, it has

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been suggested that these filters may actually increase risk by exposing the smoker to accidental ingestion or inhalation of charcoal particles present on the cut surfaces of the filter or within gaps created between the various layers of the filter wrapping paper (Pauly et al. 1997). Those authors investigated cigarettes with a triple filter by having humans smoke cigarettes through a holder equipped with a mesh screen to capture any particles, and concluded that the activated carbon particles were released during smoking. The toxicity of inhaled particles has been reviewed (Oberdo¨rster 2002); nevertheless, other work with charcoal-filtered cigarettes (Agyei-Aye et al. 2004) indicated that ‘‘only a small amount of charcoal, cellulose acetate shards, and other particles are released. It was also shown that those particles would have a low likelihood of reaching the lung”. The published literature regarding the use of charcoal in a cigarette filter conveys a ‘‘mixed message”. It is clear that impressive reductions in the concentrations for many gas–vapor phase components of mainstream cigarette smoke can be achieved by using charcoal as a component of a cigarette filter (Xue et al. 2002). Many of these smoke constituents have been identified individually as chemical irritants and/or carcinogens in a variety of studies. Nonetheless, while pre-clinical toxicity studies indicate a general reduction in the cytotoxic activity of charcoal filtered cigarette smoke suggesting a potential for a reducing respiratory inflammation and irritation, the limited epidemiology studies that have been conducted to date fail to indicate a substantial beneficial effect on lung cancer incidence from smoking charcoal filtered products. The epidemiology data on charcoal-filtration of cigarettes may itself be the cause of the Japanese paradox, because of an apparently higher background incidence of lung cancer in non-smokers than that seen in Western studies (Wakai et al. 2006), thus lowering the overall odds ratio for smoking-induced lung cancer. It is not clear why this difference from Western populations should exist; genome-wide association studies would be helpful here (Stellman et al. 2001). While possible differences between human smoking behavior and machine generated smoke is a simplistic potential explanation for the apparent paradox between experimental results and epidemiology, accurate assessment of the scientific literature is hindered due to the inconsistency in types of charcoal filters and overall product designs used between the various different disciplines (chemistry, pre-clinical, clinical and epidemiology) that have conducted studies with charcoal-filtered cigarettes. There do not appear to be any published studies using a combination of data from the different disciplines based on the same charcoal-filtered cigarette. The differences in product designs would presumably have effects on the organoleptic properties of filtered smoke. To produce a ‘‘Potentially Reduced Exposure Product”, as defined elsewhere (Institute of Medicine 2001), technologies in addition to charcoal filtration may be required.

Although charcoal filtration appears to have major effects on machine-generated smoke gas–vapor phase chemistry, with some effects in pre-clinical systems, the limited data from a single clinical study (of duration too short for the smokers to adjust) and from a single (probably underpowered) epidemiology study do not currently allow us to assume substantial risk reduction benefits to the adult smoker.

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