- Email: [email protected]
Response to “Cigarette smoke comparative toxicology”
Food and Chemical Toxicology 39 (2001) 177±180
www.elsevier.com/locate/foodchemtox
Response to ``Cigarette smoke comparative toxicology''
$
Sir Ð Dr Fitzgerald's continuing interest in our eorts to characterize the toxicity of cigarette smoke (Smith et al., 1999) is appreciated. Given that many individuals worldwide will continue to smoke cigarettes into the foreseeable future, the production of cigarettes with reduced toxicity is an important public health goal. Establishing the baseline chemical composition and toxicity pro®le for cigarettes currently on the market is necessary for measuring progress in reducing risk. Towards that goal, our group has written many peerreviewed manuscripts in which we have described the chemistry and toxicity of smoke from reference and current market cigarettes as well as a series of papers characterizing the reduced toxicity of cigarettes that primarily heat, rather than burn tobacco. Two of our more recent papers (Putnam et al., 1999; Smith et al., 2000a) in which we evaluate the toxicity and chemistry of tobacco-burning cigarettes are the focus of Dr Fitzgerald's current comments. We also appreciate Dr Fitzgerald's diligent review of the cited data in the Smith et al. (2000a) paper. He noted that B[a]P values from the Hattemeyer-Frey and Travis (1991) paper and the Waldman et al. (1991) paper were incorrectly reported. Unfortunately, a transcription error occurred in electronically transferring text from one co-author's computer system to another. This change was not noted when editing a draft of the manuscript. Although we inadvertently reported the B[a]P values published by Hattemeyer-Frey and Travis (1991), this mistake does not materially aect our discussion of their data since these authors concluded that ``cigarette smoking and indoor activities do not substantially increase human exposure to B[a]P relative to exposures to background levels of B[a]P present in the environment.'' The numerically correct B[a]P paragraph on page 374 of the discussion should read as follows: Although B[a]P is found in cigarette mainstream smoke at very low levels, the non-smoking general population is exposed to this PAH from many sources, including air pollution from engine exhaust gases, water, soil and many heated foodstus (ATSDR, 1990a). Currently, OSHA permits 0.2 mg/m3 of B[a]P over an 8-hour work shift. $
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Although it is generally considered that most B[a]P enters the body via the respiratory tract, considerable data indicate that other exposure routes may predominate. For example, an analysis of daily exposure to B[a]P revealed that the range and magnitude of dietary exposures ranged from 2 to 500 ng/day and were much greater than those for inhalation at 10 to 50 ng/day (Waldman et al., 1991). In another study, the B[a]P exposure was found to be 2.2 mg/day (2200 ng/day) of which 97% resulted from dietary exposure, 3% from inhalation (Hattemeyer-Frey and Travis, 1991). However, neither of these studies included B[a]P exposure from beverages such as coee and tea whose B[a]P content had been known since the 1950s. B[a]P is one of the ®ve PAHs most commonly found in foodstus (Grasso, 1984). Also, Dr Fitzgerald comments on the issue of whether ``animal cancer studies reveal a threshold of B[a]P eect.'' As discussed in our text, the situation for B[a]P is not unique. A threshold value for numerous tumorigens has been reported, for example, DB[a,h]A (DobrowolskaõÈa-ZavadskaõÈa, 1938), B[a]P by dermal assay (Horton and Denman, 1955; Poel, 1956; Poel and Kammer, 1956), various amines, and cigarette smoke condensate (Wynder et al., 1957b). The threshold limit value for B[a]P in a skin-painting bioassay was con®rmed by Wynder et al. (1957a), the same year they reported that CSC also showed a threshold limit value (Wynder et al., 1957b). This threshold limit value for CSC in an animal bioassay was proposed as a means to control respiratory tract cancer in smokers (Wynder, 1957). Their report on the threshold limit value of CSC triggered extensive US Tobacco Industry R&D eorts which ultimately led to the development of the various cigarette design technologies that resulted in the gradual reduction in cigarette mainstream smoke (MS) salesweighted average ``tar'' delivery by the Tobacco Industry from about 40 mg/cigarette in the late 1950s to the current 11 mg/cigarette. Dr Fitzgerald's reference to B[a]P as ``potently mutagenic'' can be put into perspective by comparing B[a]P with other compounds, particularly those containing nitrogen. For example, the mutagenicity in Ames Salmonella bacterial strain TA98 for the heterocyclic amine
0278-6915/01/$ - see front matter # 2001 Elsevier Science Ltd. All rights reserved. PII: S0278-6915(00)00129-0
178
Letter to the Editor / Food and Chemical Toxicology 39 (2001) 177±180
MeIQ has been reported to be 2065 times higher than that measured for B[a]P (Smith et al., 1992). At one time the US NCI stated that the threshold limit for a tumorigen was exposure to a single molecule of the compound. Subsequently, this view of a threshold limit value for a tumorigen was discarded. In addition, Dr Fitzgerald takes issue with the statement that the TLV (on the basis of cancer bioassay) is the equivalent of the B[a]P content of ``the mainstream smoke from several hundred cigarettes.'' We are pleased to see that Dr Fitzgerald has a problem with such an extrapolation. For many years, numerous investigators ignored the caution urged by Shear and Leiter (1941) in the assessment of results of experiments in carcinogenesis. From the date of the ®rst successful experiments in carcinogenesis on the skin of a susceptible mouse strain painted repeatedly with an unusually high dose of CSC (Wynder et al., 1953), it has been intimated that the mouse skin-painting data are relevant to the human smoker respiratory tract situation. Examination of the caution outlined by Shear and Leiter (1941) reveals that one should not extrapolate a ®nding on the dermal tissue of a mouse treated with a concentrated solution of CSC to the lung tissue of a smoker who is inhaling an aerosol comprising a vapour and particulate phase. Such a comparison involves dierences in species, strains, tissue type, dosage, means of administration, mechanism of tissue protection, and other variables. Dr Fitzgerald may be familiar with published reports classifying the phenols (phenol, cresols, xylenols) in MS as signi®cant non-tumorigenic promoters of PAH tumorigenesis. However, Homann and Wynder (1963) reported that almost complete removal of the promoting phenols from MS resulted in no change in the speci®c tumorigenicity of the CSC. Thus, the experimental evidence suggests that phenols classi®ed by many investigators as signi®cant promoters apparently fail to promote. In addition, Van Duuren et al. (1971) reported that phenol, reported by some investigators to be a signi®cant promoter of MS B[a]P tumorigenesis, inhibited the speci®c tumorigenicity of B[a]P. While noting the possible eect of promoters on the tumorigenicity of various compounds in MS, Dr. Fitzgerald did not mention the substantial number of MS components known to inhibit the tumorigenicity of PAHs, N-nitrosamines, heterocyclic amines, etc. Many of these inhibitory components are present in MS in sucient concentration vs the tumorigens to exert their inhibition or antitumorigenicity. For example, several long-chained saturated hydrocarbons present in MS were reported to be signi®cant inhibitors of the speci®c tumorigenicity of B[a]P (Wynder and Homann, 1962, 1967). Since the 1950s, many examples have been reported in which a low molecular weight non-tumorigenic PAH administered with a potently tumorigenic PAH in a 1:1 mol ratio was found to signi®cantly inhibit the tumorigenicity
of the tumorigenic PAH. These same non-tumorigenic PAHs are present in MS but their mol ratios are much greater than the 1:1 ratio noted. Other examples are noted by Homburger et al. (1968), Huber (1989) and Rodgman (1991, 1992, 1994). Correctly, Dr Fitzgerald has pointed out that several values for dietary heterocyclic amines are erroneously reported. These errors were due to the same computer software transpositions previously discussed. The values listed should have been mg/day not mg/day. The corrected text should read as follows: The major source of the N-heterocyclic amine IQ is muscle meats cooked at high temperatures. It has also been reported in cigarette mainstream smoke. The human intake of the eight major N-heterocyclic amines, including IQ, is relatively high, averaging between 10 and 20 mg/day. However, Sugimura (1986) estimated from the TD50 values obtained with mice fed seven dierent N-heterocyclic amines (IQ, Trp-P-1, Trp-P-2, Glu-P-1, Glu-P-2, AC, MeAC) and from their levels in foods consumed by humans that the human intake is only 0.0002% of the TD50 obtained from animal data. Although IQ has been classi®ed as a potent Ames Salmonella mutagen (Smith et al., 1992), IQ has also been reported to be a very weak mutagen in several mammalian cell tests at the aprt and hprt loci of UV5 Chinese hamster ovary cells reverted to possess normal levels of DNA excision repair (Thompson et al., 1991). IQ was somewhat more mutagenic in derivatives of these cells expressing P450 and de®cient in excision repair. Adamson et al. (1991) have reported long-term toxicity of IQ in primates and rodents. At both low and high doses, liver cancer occurred in monkeys. The average latency period was 43 to 60 months. Thorgeirsson et al. (1993) reported similar results in monkeys exposed to two lower doses (10 mg/kg or 20 mg/kg) 5 days per week for 48 to 80 months. The dose levels of IQ investigated in these studies are enormous compared with the per cigarette MS deliveries of IQ in the subnanogram/ cigarette range. The monkeys had cardiac lesions but no heart damage. It was suggested that long-term exposure to IQ at high doses might cause heart damage. Also regarding the Smith et al. (2000a) paper, we are cognizant of the highly interactive nature of chemicals in complex mixtures and recognize that a simple tabulation of individual chemicals cannot be used to predict the toxicity of cigarette smoke. In the absence of relevant biological testing data, we neither state nor imply that addition or removal of a given chemical constituent or family of constituents will necessarily alter toxicity. In fact, we have published several papers that describe the interactive eects of smoke constituents in toxicology
Letter to the Editor / Food and Chemical Toxicology 39 (2001) 177±180
assays (Lee et al., 1989, 1996; Brown et al., 1998). Nevertheless, identi®cation of the potentially toxic chemicals in cigarette smoke (Smith et al., 1997, 2000a,b) will facilitate eorts to reduce the toxicity of cigarette smoke through product modi®cation. In summary, although we endeavour to accurately cite the work of other scientists, in this instance an undetected incompatibility in the computer software used by co-authors led to several inadvertent transcription errors, thereby transposing mg to mg. We appreciate Dr Fitzgerald taking sucient interest in our work to discover these errors and providing the opportunity to correct the record. Finally, we would like to address his incorrect assertion regarding our conclusion based on the Putnam et al. (1999) paper data. We did not ``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.'' Our conclusion is stated in the last paragraph of the paper as ``The results of these studies clearly indicate that complex mixtures derived from dierent sources of pyrolysis dier in their cytotoxic and mutagenic potential. Further toxicological studies of various pyrolysis products, combined with examination of the chemical composition of the mixtures, will lead to a better understanding of the toxic mechanisms.'' Please note that the numerical errors that occurred due to the transfer of information between computers have also appeared in a recent manuscript describing the ``IARC Group 2B Carcinogens'' reported in cigarette mainstream smoke (Smith et al., 2000b). Appropriate errata will be published regarding the errors in both the IARC Group 2A and Group 2B literature surveys on cigarette mainstream smoke.
References Adamson, R.H., Snyderwine, E.G., Thorgeirsson, U.P., Schut, H.A.J., Turesky, R.J., Thorgeirsson, S.S., Takayama, S., Sugimura, S., 1991. Metabolic processing and carcinogenicity of heterocyclic amines in nonhuman primates. Princess Takamatsu Symposium 21, 289±301. ATSDR, 1990a. ATSDR Public Heaalth Statement: Benzo[a]pyrene. Agency for Toxic Substances and Disease Registry http:// www.atsdr.cdc.gov:8080/ToxPro®les/phs8805.html. May 1990. Brown, B.G., Kolesar, J., Lindberg, K., Meckley, D., Mosberg, A.T., Doolittle, D.J., 1998. Comparative studies of DNA adduct formation in mice following dermal application of smoke condensates from cigarettes that burn or primarily heat tobacco. Mutation Research 30, 414±421. DobrowolskaõÈa-ZavadskaõÈa, N., 1938. Doses of 1,2,5,6-dibenzanthracene capable of producing cancer in mice. Comptes Rendus de la SocieÂte Biologique (France) 129, 1055±1057. Grasso, P., 1984. Carcinogens in food. In Chemical Carcinogens, Second Edition, ed. C.E. Searle, pp. 1205±1239. American Chemical
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Society Monograph 182, American Chemical Society, Washington, DC. Hattemeyer-Frey, H.A., Travis, C.C., 1991. Benzo-a-pyrene [sic]: Environmental partitioning and human exposure. Toxicology and Industrial Health 7, 141±157. Homann, D., Wynder, E.L., 1963. Die Filtration von Phenol aus Cigarettenrauch. BeitraÈge zur Tabakforschung 2, 51±56 , (Filtration of phenols from cigarette smoke. Journal of the National Cancer Institute 30, 67±84). Homburger, F., Treger, A., Boger, E., 1968. Experimental studies on the inhibition of carcinogenesis by cigarette-smoke condensates and carcinogen-related substances. In: Wynder, E.L., Homann, D., Toward a Less Harmful Cigarette. National Cancer Institute Monograph 28, 259±270. Horton, A.W., Denman, D.T., 1955. Carcinogenesis of the skin Ð a re-examination of methods for the quantitative measurement of the potencies of complex materials. Cancer Research 15, 701±709. Huber, G.L., 1989. Physical, chemical and biological properties of tobacco, cigarette smoke, and other tobacco products. In: Huber, G.L. Tobacco and Smoking Cessation. I. Seminars in Respiratory Medicine, vol. 10, pp. 297±332 (see p. 312, Table 5). Lee, C.K., Munoz, J.A., Fulp, C.W., Chang, K.M., Rogers, J., Borgerding, M.F., Doolittle, D.J., 1989. Inhibitory activity of cigarettesmoke condensate on the mutagenicity of heterocyclic amines. Mutation Research 322, 21±32. Lee, C.K., Fulp, C.W, Bombick, B.R., Doolittle, D.J., 1996. Inhibition of mutagenicity of N-nitrosamines by tobacco smoke and its constituents. Mutation Research 92, 367±383. Poel, W.E., 1956. Carcinogens and minimal carcinogenic doses. Science 123, 588. Poel, W.E., Kammer, A.G., 1958. Preliminary studies in a quantitative approach to skin carcinogenesis. Journal of the National Cancer Institute 16, 989±994. Putnam, K.P., Bombick, D.W., Avalos, J.T., Doolittle, D.J., 1999. Comparison of the cytotoxic and mutagenic potential of liquid smoke food ¯avorings, cigarette smoke condensates and wood smoke condensate. Food and Chemical Toxicology 37, 1113±1118. Rodgman, A., 1991. A comparison of the chemical and physical properties of cigarette mainstream smoke (MS), cigarette sidestream smoke (SS), and environmental tobacco (ETS). Document submitted to the Environmental Protection Agency, December 1991, revised version submitted, June 1992, pp. vii+116. Rodgman, A., 1992. Environmental tobacco smoke. Regulatory Toxicology and Pharmacology 16, 223±244. Rodgman, A., 1994. The chemical composition of environmental tobacco smoke: some comments on the Occupational Safety and Health Administration's notice on ``Indoor air quality.'' Document submitted to the Occupational Safety and Health Administration, 5 August 1994, pp. xiii+172. Shear, M.J., Leiter, J., 1941. Studies in carcinogenesis. XVI. Production of subcutaneous tumors in mice by miscellaneous polycyclic compounds. Journal of the National Cancer Institute 2, 241±258 (Pertinent details are included in Introduction in Hartwell J.L. (1951) Survey of Compounds Which Have Been Tested for Carcinogenic Activity. USPHS Publication No. 149, 2nd Edition, Washington, DC). Smith, C.J., Payne, V.M., Doolittle, D.J., Debnath, A.K., Lawlor, T., Hansch, C., 1992. Mutagenic activity of a series of synthetic and naturally occurring heterocyclic amines in Salmonella. Mutation Research 279, 61±73. Smith, C.J., Livingston, S.D., Doolittle, D.J., 1997. An international literature survey of ``IARC Group 1 Carcinogens'' reported in mainstream cigarette smoke. Food and Chemical Toxicology 35, 1107±1130. Smith, C.J., Livingston, S.D., Doolittle, D.J., 1999. Response to D.J. Fitzgerald's letter to editor regarding ``IARC Group 1 Carcinogens'' in tobacco smoke. Food and Chemical Toxicology 37, 265±266.
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Smith, C.J., Perfetti, T.A., Rumple, M.A., Rodgman, A., Doolittle, D.J., 2000a. ``IARC Group 2A Carcinogens'' reported in cigarette mainstream smoke. Food and Chemical Toxicology 38, 371±383. Smith, C.J., Perfetti, T.A., Rumple, M.A., Rodgman, A., Doolittle, D.J., 2000b. ``IARC Group 2B Carcinogens'' reported in cigarette mainstream smoke. Food and Chemical Toxicology 38, 825±848. Sugimura, T., 1986. Past, present and future of mutagens in cooked foods. Environmental Health Perspectives 67, 5±10. Thompson, L.H., Wu, R.W., Felton, J.S., 1991. Introduction of cytochrome P450IA2 metabolic capability into cell lines genetically matched for DNA repair pro®ciency/de®ciency. Proceedings of the National Academy of Sciences, U.S.A. 88, 3827±3833. Thorgeirsson, U.P., Farb, A., Virmani, R., Adamson, R.H., 1993. Cardiac damage induced by 2-amino-3-methylimidazo[4,5-f ]quinoline in nonhuman primates. Environmental Health Perspectives 102, 194. Van Duuren, B.L., Sivak, A., Katz, C., Melchionne, S., 1971. Cigarette smoke carcinogenesis: Importance of tumor promoters. Journal of the National Cancer Institute 47, 235±240. Waldman, J.M., Lioy, P.J., Greenberg, A., Butler, J.P., 1991. Analysis of human exposure to benzo(a)pyrene [sic] via inhalation and food ingestion in the total human exposure study (THEES). Journal of Experimental Analysis of Environmental Epidemiology 1, 93±225. Wynder, E.L., 1957. Statement on the lung cancer-cigarette smoking controversy: Chemical fractionation of cigarette smoke. In: False and Misleading Advertising (Filter-Tip Cigarettes). Hearing before Subcommittee of the Committee on Government Operations, House of Representatives, 85th Congress, 1st Session, p. 104. PII: S0278-6915(00)00129-0
Wynder, E.L., Homann, D., 1962. Studies with the gaseous and particulate phase of tobacco smoke. Proceedings of the American Association for Cancer Research 3 (4), 373 (Tobacco and Tobacco Smoke: Studies in Experimental Carcinogenesis. Academic Press, New York, 1967, p. 370). Wynder, E.L., Homann, D., 1967. Tobacco and Tobacco Smoke: Studies in Experimental Carcinogenesis. Academic Press, New York. Wynder, E.L., Graham, E.A., Croninger, A.B., 1953. Study on the experimental production of cancer with tobacco tar. Proceedings of the American Association for Cancer Research 3 (1), 62-63 (Experimental production of carcinoma with cigarette tar. Cancer Research 13, 855-864). Wynder, E.L., Fritz, L., Furth, N., 1957a. Eect of concentration of benzopyrene in skin carcinogenesis. Journal of the National Cancer Institute 19, 361±370. Wynder, E.L., Kopf, P., Ziegler, H., 1957b. A study of tobacco carcinogenesis. II. Dose±response studies. Cancer 10, 1193±1200.
C.J. Smith, T.A. Perfetti, D.W. Bombick A. Rodgman, D.J. Doolittle Research & Development Bowman Gray Technical Center R. J. Reynolds Tobacco Company Winston-Salem NC 27102, USA E-mail address: [email protected]
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Response to ``Cigarette smoke comparative toxicology''
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Sir Ð Dr Fitzgerald's continuing interest in our eorts to characterize the toxicity of cigarette smoke (Smith et al., 1999) is appreciated. Given that many individuals worldwide will continue to smoke cigarettes into the foreseeable future, the production of cigarettes with reduced toxicity is an important public health goal. Establishing the baseline chemical composition and toxicity pro®le for cigarettes currently on the market is necessary for measuring progress in reducing risk. Towards that goal, our group has written many peerreviewed manuscripts in which we have described the chemistry and toxicity of smoke from reference and current market cigarettes as well as a series of papers characterizing the reduced toxicity of cigarettes that primarily heat, rather than burn tobacco. Two of our more recent papers (Putnam et al., 1999; Smith et al., 2000a) in which we evaluate the toxicity and chemistry of tobacco-burning cigarettes are the focus of Dr Fitzgerald's current comments. We also appreciate Dr Fitzgerald's diligent review of the cited data in the Smith et al. (2000a) paper. He noted that B[a]P values from the Hattemeyer-Frey and Travis (1991) paper and the Waldman et al. (1991) paper were incorrectly reported. Unfortunately, a transcription error occurred in electronically transferring text from one co-author's computer system to another. This change was not noted when editing a draft of the manuscript. Although we inadvertently reported the B[a]P values published by Hattemeyer-Frey and Travis (1991), this mistake does not materially aect our discussion of their data since these authors concluded that ``cigarette smoking and indoor activities do not substantially increase human exposure to B[a]P relative to exposures to background levels of B[a]P present in the environment.'' The numerically correct B[a]P paragraph on page 374 of the discussion should read as follows: Although B[a]P is found in cigarette mainstream smoke at very low levels, the non-smoking general population is exposed to this PAH from many sources, including air pollution from engine exhaust gases, water, soil and many heated foodstus (ATSDR, 1990a). Currently, OSHA permits 0.2 mg/m3 of B[a]P over an 8-hour work shift. $
PII of original article:S0278-6915(00)00128-9
Although it is generally considered that most B[a]P enters the body via the respiratory tract, considerable data indicate that other exposure routes may predominate. For example, an analysis of daily exposure to B[a]P revealed that the range and magnitude of dietary exposures ranged from 2 to 500 ng/day and were much greater than those for inhalation at 10 to 50 ng/day (Waldman et al., 1991). In another study, the B[a]P exposure was found to be 2.2 mg/day (2200 ng/day) of which 97% resulted from dietary exposure, 3% from inhalation (Hattemeyer-Frey and Travis, 1991). However, neither of these studies included B[a]P exposure from beverages such as coee and tea whose B[a]P content had been known since the 1950s. B[a]P is one of the ®ve PAHs most commonly found in foodstus (Grasso, 1984). Also, Dr Fitzgerald comments on the issue of whether ``animal cancer studies reveal a threshold of B[a]P eect.'' As discussed in our text, the situation for B[a]P is not unique. A threshold value for numerous tumorigens has been reported, for example, DB[a,h]A (DobrowolskaõÈa-ZavadskaõÈa, 1938), B[a]P by dermal assay (Horton and Denman, 1955; Poel, 1956; Poel and Kammer, 1956), various amines, and cigarette smoke condensate (Wynder et al., 1957b). The threshold limit value for B[a]P in a skin-painting bioassay was con®rmed by Wynder et al. (1957a), the same year they reported that CSC also showed a threshold limit value (Wynder et al., 1957b). This threshold limit value for CSC in an animal bioassay was proposed as a means to control respiratory tract cancer in smokers (Wynder, 1957). Their report on the threshold limit value of CSC triggered extensive US Tobacco Industry R&D eorts which ultimately led to the development of the various cigarette design technologies that resulted in the gradual reduction in cigarette mainstream smoke (MS) salesweighted average ``tar'' delivery by the Tobacco Industry from about 40 mg/cigarette in the late 1950s to the current 11 mg/cigarette. Dr Fitzgerald's reference to B[a]P as ``potently mutagenic'' can be put into perspective by comparing B[a]P with other compounds, particularly those containing nitrogen. For example, the mutagenicity in Ames Salmonella bacterial strain TA98 for the heterocyclic amine
0278-6915/01/$ - see front matter # 2001 Elsevier Science Ltd. All rights reserved. PII: S0278-6915(00)00129-0
178
Letter to the Editor / Food and Chemical Toxicology 39 (2001) 177±180
MeIQ has been reported to be 2065 times higher than that measured for B[a]P (Smith et al., 1992). At one time the US NCI stated that the threshold limit for a tumorigen was exposure to a single molecule of the compound. Subsequently, this view of a threshold limit value for a tumorigen was discarded. In addition, Dr Fitzgerald takes issue with the statement that the TLV (on the basis of cancer bioassay) is the equivalent of the B[a]P content of ``the mainstream smoke from several hundred cigarettes.'' We are pleased to see that Dr Fitzgerald has a problem with such an extrapolation. For many years, numerous investigators ignored the caution urged by Shear and Leiter (1941) in the assessment of results of experiments in carcinogenesis. From the date of the ®rst successful experiments in carcinogenesis on the skin of a susceptible mouse strain painted repeatedly with an unusually high dose of CSC (Wynder et al., 1953), it has been intimated that the mouse skin-painting data are relevant to the human smoker respiratory tract situation. Examination of the caution outlined by Shear and Leiter (1941) reveals that one should not extrapolate a ®nding on the dermal tissue of a mouse treated with a concentrated solution of CSC to the lung tissue of a smoker who is inhaling an aerosol comprising a vapour and particulate phase. Such a comparison involves dierences in species, strains, tissue type, dosage, means of administration, mechanism of tissue protection, and other variables. Dr Fitzgerald may be familiar with published reports classifying the phenols (phenol, cresols, xylenols) in MS as signi®cant non-tumorigenic promoters of PAH tumorigenesis. However, Homann and Wynder (1963) reported that almost complete removal of the promoting phenols from MS resulted in no change in the speci®c tumorigenicity of the CSC. Thus, the experimental evidence suggests that phenols classi®ed by many investigators as signi®cant promoters apparently fail to promote. In addition, Van Duuren et al. (1971) reported that phenol, reported by some investigators to be a signi®cant promoter of MS B[a]P tumorigenesis, inhibited the speci®c tumorigenicity of B[a]P. While noting the possible eect of promoters on the tumorigenicity of various compounds in MS, Dr. Fitzgerald did not mention the substantial number of MS components known to inhibit the tumorigenicity of PAHs, N-nitrosamines, heterocyclic amines, etc. Many of these inhibitory components are present in MS in sucient concentration vs the tumorigens to exert their inhibition or antitumorigenicity. For example, several long-chained saturated hydrocarbons present in MS were reported to be signi®cant inhibitors of the speci®c tumorigenicity of B[a]P (Wynder and Homann, 1962, 1967). Since the 1950s, many examples have been reported in which a low molecular weight non-tumorigenic PAH administered with a potently tumorigenic PAH in a 1:1 mol ratio was found to signi®cantly inhibit the tumorigenicity
of the tumorigenic PAH. These same non-tumorigenic PAHs are present in MS but their mol ratios are much greater than the 1:1 ratio noted. Other examples are noted by Homburger et al. (1968), Huber (1989) and Rodgman (1991, 1992, 1994). Correctly, Dr Fitzgerald has pointed out that several values for dietary heterocyclic amines are erroneously reported. These errors were due to the same computer software transpositions previously discussed. The values listed should have been mg/day not mg/day. The corrected text should read as follows: The major source of the N-heterocyclic amine IQ is muscle meats cooked at high temperatures. It has also been reported in cigarette mainstream smoke. The human intake of the eight major N-heterocyclic amines, including IQ, is relatively high, averaging between 10 and 20 mg/day. However, Sugimura (1986) estimated from the TD50 values obtained with mice fed seven dierent N-heterocyclic amines (IQ, Trp-P-1, Trp-P-2, Glu-P-1, Glu-P-2, AC, MeAC) and from their levels in foods consumed by humans that the human intake is only 0.0002% of the TD50 obtained from animal data. Although IQ has been classi®ed as a potent Ames Salmonella mutagen (Smith et al., 1992), IQ has also been reported to be a very weak mutagen in several mammalian cell tests at the aprt and hprt loci of UV5 Chinese hamster ovary cells reverted to possess normal levels of DNA excision repair (Thompson et al., 1991). IQ was somewhat more mutagenic in derivatives of these cells expressing P450 and de®cient in excision repair. Adamson et al. (1991) have reported long-term toxicity of IQ in primates and rodents. At both low and high doses, liver cancer occurred in monkeys. The average latency period was 43 to 60 months. Thorgeirsson et al. (1993) reported similar results in monkeys exposed to two lower doses (10 mg/kg or 20 mg/kg) 5 days per week for 48 to 80 months. The dose levels of IQ investigated in these studies are enormous compared with the per cigarette MS deliveries of IQ in the subnanogram/ cigarette range. The monkeys had cardiac lesions but no heart damage. It was suggested that long-term exposure to IQ at high doses might cause heart damage. Also regarding the Smith et al. (2000a) paper, we are cognizant of the highly interactive nature of chemicals in complex mixtures and recognize that a simple tabulation of individual chemicals cannot be used to predict the toxicity of cigarette smoke. In the absence of relevant biological testing data, we neither state nor imply that addition or removal of a given chemical constituent or family of constituents will necessarily alter toxicity. In fact, we have published several papers that describe the interactive eects of smoke constituents in toxicology
Letter to the Editor / Food and Chemical Toxicology 39 (2001) 177±180
assays (Lee et al., 1989, 1996; Brown et al., 1998). Nevertheless, identi®cation of the potentially toxic chemicals in cigarette smoke (Smith et al., 1997, 2000a,b) will facilitate eorts to reduce the toxicity of cigarette smoke through product modi®cation. In summary, although we endeavour to accurately cite the work of other scientists, in this instance an undetected incompatibility in the computer software used by co-authors led to several inadvertent transcription errors, thereby transposing mg to mg. We appreciate Dr Fitzgerald taking sucient interest in our work to discover these errors and providing the opportunity to correct the record. Finally, we would like to address his incorrect assertion regarding our conclusion based on the Putnam et al. (1999) paper data. We did not ``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.'' Our conclusion is stated in the last paragraph of the paper as ``The results of these studies clearly indicate that complex mixtures derived from dierent sources of pyrolysis dier in their cytotoxic and mutagenic potential. Further toxicological studies of various pyrolysis products, combined with examination of the chemical composition of the mixtures, will lead to a better understanding of the toxic mechanisms.'' Please note that the numerical errors that occurred due to the transfer of information between computers have also appeared in a recent manuscript describing the ``IARC Group 2B Carcinogens'' reported in cigarette mainstream smoke (Smith et al., 2000b). Appropriate errata will be published regarding the errors in both the IARC Group 2A and Group 2B literature surveys on cigarette mainstream smoke.
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C.J. Smith, T.A. Perfetti, D.W. Bombick A. Rodgman, D.J. Doolittle Research & Development Bowman Gray Technical Center R. J. Reynolds Tobacco Company Winston-Salem NC 27102, USA E-mail address: [email protected]