Cigarette smoke comparative toxicology

Cigarette smoke comparative toxicology

Food and Chemical Toxicology 39 (2001) 175±176 www.elsevier.com/locate/foodchemtox Letter to the Editor Cigarette smoke comparative toxicology Sir ...

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Food and Chemical Toxicology 39 (2001) 175±176

www.elsevier.com/locate/foodchemtox

Letter to the Editor

Cigarette smoke comparative toxicology Sir Ð I am writing to redress some misunderstandings that may arise from two recent papers relating to cigarette smoke, published in this journal by the group of David Doolittle at R.J. Reynolds Tobacco Company. I believe that these papers present some misleading comparisons, and the basis for this opinion is discussed here. In the ®rst paper, the authors employed a dye uptake cytotoxicity assay with CHO cells and Ames bacterial mutagenicity assays to compare toxicological activity of cigarette smoke condensate (CSC) with that of four liquid smoke food ¯avourings (LSF) and a wood smoke condensate (WSC) (Putnam et al., 1999). The cytotoxicity dose±response data showed that on a weight basis, one LSF was less toxic, WSC had similar toxicity, and three LSF were more toxic than CSC. An inference that could be drawn is that LSF and WSC ought to be viewed as posing public health concern, and indeed health experts need to be aware of dietary and environmental exposures which are potentially hazardous. On the other hand, the authors may have intended to suggest that cigarette smoke ought not to be viewed as particularly dangerous since, on a relative basis, CSC in the present study was no more toxic than condensate material associated with common and accepted exposures such as wood smoke and food ¯avourings. However, the authors would appreciate that risk assessment encompasses consideration of not just innate toxicity of a chemical or mixture but also of dose and exposure frequency. As such, active cigarette smoke inhalation by a frequent smoker would be far more injurious to human tissue than the infrequent exposure of most populations to wood smoke or smoke food ¯avourings. Concerning the other data set in this paper, namely induction of bacterial mutagenicity, the authors devote scant discussion to their data in Table 3, which show that only CSC caused mutations in TA98 with and without S9 and that CSC was the most potent mutagen towards TA100 with S9. It would seem remiss that the authors, who have used relative terms to highlight the comparable cytotoxicity of various other condensates with that of CSC, have not similarly used relative terms to describe the mutagenicity status of CSC in this study. The authors may not be aware that recent correspondence in the international literature is calling for cigarette manufacturers to accurately describe the toxicity of

their products to consumers (Wilkenfeld et al., 2000). This call should also apply where industry scientists are dealing with comparative toxicology. The second paper, entitled ``IARC Group 2A carcinogens'' reported in cigarette mainstream smoke'', examines the documented levels in cigarette smoke of nine chemicals classi®ed by the International Agency for Research on Cancer (IARC) as probable human carcinogens (Smith et al., 2000). In addition, the paper sets out to make a range of comparisons with other exposures, such as dietary, to these same carcinogens. However, several errors in citation and logic are apparent. For example, in discussing the ubiquitous benzo[a]pyrene (BaP), the authors claim that one study (Waldman et al., 1991) reports dietary exposures of 2000 to 500,000 mg/day among study subjects and inhalational exposures of 10,000±50,000 mg/day. Perusal of this cited paper reveals that dietary exposures were, in fact, 2±500 ng/day and inhalational exposures were 10±50 ng/day. In the context of the authors' own table showing that cigarette smoke contains up to 100 ng BaP per cigarette (Smith et al., 2000), this now becomes by far the major exposure of smokers to this potent carcinogen. The authors next cite a study which they state reports that average daily dietary exposure to BaP is 97% of a total intake of 2,200,000 mg/day (Hattemer-Frey and Travis, 1991). This is incorrect, since the paper actually reports the average daily intake (for the general US population) as 2.2 mg/day. In comparison here also, the BaP content of cigarette smoke provides a major exposure circumstance. Following on in the BaP discussion, the authors state that animal cancer studies reveal a threshold of BaP e€ect. This is in one sense true since even the most potent mutagen or carcinogen ever tested will show an apparent threshold simply because of the limitation in the number of animals that can be practically used in cancer bioassays. However, no smoker (or potential smoker) should ever be led to believe that there is a safe level of exposure of lung tissue to the potently mutagenic BaP. The authors then claim that the threshold limit value (on the basis of a cancer bioassay) is the equivalent of the BaP content of ``the mainstream smoke from several hundred cigarettes''. Three points here: ®rst, this is an odd extrapolation to a human lung BaP

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Letter to the Editor / Food and Chemical Toxicology 39 (2001) 175±176

exposure scenario from the cited mouse skin cancer study (Wynder et al., 1957); secondly, this would represent an admission by the authors that every serious smoker exceeds this threshold by at least two orders of magnitude every year; and thirdly, discussion of studies where BaP alone was tested ignores a whole body of evidence showing that experimental subthreshold doses of mutagenic carcinogens can result in initiation of the cancer process which becomes manifest upon chronic exposure to noncarcinogenic tumour promoters. Cigarette smoke is known to contain many such tumour-promoting chemicals. One further instance of an incorrect comparison drawn by Smith and colleagues is found in their discussion of 2-amino-3-methyl-3H-imidazo[4,5-f]quinoline (IQ). They claim that the human dietary intake of IQ and the other major N-heterocyclic amines (HA) averages 10 to 20 mg/day (no ref. given). However, a recent review on the topic in this journal indicates that HA intake is in the order of 1±20 mg/day (Skog et al., 1998). Even the 1986 Sugimura paper which the authors go on to discuss (and from which they maltranscribe his HA-TD50 as an LD50), provides an estimate of daily HA intake that is one to two orders of magnitude less than the authors' assertion. In any case, for a fair comparison, the authors ought to have commented on the known levels of carcinogenic HA in cigarette mainstream smoke. According to IARC documents and references utilized by the authors, levels of IQ, PhIP, AaC and MeAaC found in cigarette smoke condensate are, respectively, 0.2±0.5, 11± 23, 25±258 and 6±37 ng/cigarette. (Evidence for carcinogenicity in experimental animals has been deemed sucient by IARC for each of these chemicals.) Addition of these ranges shows that, with 20 cigarettes per day, a smoker can be exposed to 844±6370 ng/day of carcinogenic HA, i.e. about 1 to 6 mg/day. Thus, in a proper comparison with HA in food (1±20 mg/day), it is clear that carcinogenic HA in cigarette smoke represents a similar additional exposure to HA and one which is certainly not comparatively insigni®cant as the authors suggest. Therefore, with this paper also, wrong information provided by the authors means that the scienti®c comPII: S0278-6915(00)00128-9

munity and the public are given misleading toxicological comparisons. Since hopes by the tobacco industry for widespread release and acceptance of new technology non-pyrolysis cigarettes have not and may not be realized, it is incumbent on the industry to employ unabashed scienti®c rigor in describing the characteristics and toxicology of mainstream smoke from current technology cigarettes. References Hattemer-Frey, H.A., Travis, C.C., 1991. Benzo-a-pyrene: environmental partitioning and human exposure. Toxicology and Industrial Health 7, 141±157. Putnam, K.P., Bombick, D.W., Avalos, J.T., Doolittle, D.J., 1999. Comparison of the cytotoxic and mutagenic potential of liquid smoke food ¯avourings, cigarette smoke condensate and wood smoke condensate. Food and Chemical Toxicology 37, 1113±1118. Skog, K.I., Johansson, M.A.E., JaÈgerstad, M.I., 1998. Carcinogenic heterocyclic amines in model systems and cooked foods: A review on formation, occurrence and intake. Food and Chemical Toxicology 36, 879±896. Smith, C.J., Perfetti, T.A., Rumple, M.A., Rodgman, A., Doolittle, D.J., 2000. ``IARC Group 2A carcinogens'' reported in cigarette mainstream smoke. Food and Chemical Toxicology 38, 371±383. Sugimura, T., 1986. Past, present, and future of mutagens in cooked foods. Environmental Health Perspectives 67, 5±10. Waldman, J.M., Lioy, P.J., Greenberg, A., Butler, J.P., 1991. Analysis of human exposure to benzo(a)pyrene via inhalation and food ingestion in the Total Human Environmental Exposure Study (THEES). Journal of Exposure Analysis and Environmental Epidemiology 1, 193±225. Wilkenfeld, J., Henning®eld, J., Slade, J., Burns, D., Pinney, J., 2000. It's time for a change: cigarette smokers deserve meaningful information about their cigarettes. Journal of the National Cancer Institute 92, 90±92. Wynder, E.L., Fritz, L., Furth, N., 1957. E€ect of concentration of benzopyrene in skin carcinogenesis. Journal of the National Cancer Institute 19, 361±370.

Dr J. Fitzgerald Environmental Health Branch Department of Human Services, PO Box 6, Rundle Mall Adelaide, South Australia 5000, Australia E-mail address: jim.®[email protected]