Fractionation of mouse skin carcinogens in cigarette smoke condensate

P, Lee; Rothwell, K.; Whitehead, J. K.

doi:10.1038/bjc.1977.114

Cited by 11 publications

(6 citation statements)

References 9 publications

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“…Finally, in an analysis of data from over 7000 mice treated regularly throughout life with various cigarette smoke fractions, Lee et al (1977) report the incidence rates of carcinomas to be proportional to The point I wish to emphasize in all these sets of data is that if we write ðincidence rateÞ / ð dose rateÞ a Á ð durationÞ b then (b þ 1)/a is more like 2 or 3 than unity, a statement which is also supported by the data of Druckrey (1967) on carcinogenesis in rats induced by nitrosamines. 19 Now a is whose "spontaneous" death rates are much larger.…”

Section: Disparity Between the Exponents Of Dose And Timementioning

confidence: 99%

Epidemiology, multistage models, and short-term mutagenicity tests

Pető¹

2016

Int. J. Epidemiol.

100

107

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This section is intended as an introduction to, and apology for, multistage models. Such models occupy a curious position in the world of cancer research. It seems likely that multistage processes underlie the generation of a large majority of human cancers (the carcinomas), yet most research workers do not have any real interest in discussing the various alternative multistage models that attempt to describe these processes. These research workers can't all be wrong, so what is wrong with multistage models? The trouble is, I suppose, that the processes usually invoked are, in principle, extremely difficult to observe (phenotypically silent changes in a few scattered somatic cells), and that very similar predictions for the few things we can actually observe may follow from mathematical elaboration of various very different multistage models (each with its own implausible chalones, feedback mechanisms, exact numbers of "stages" to be progressed through, mutations, epigenetic switches, clonal growth rates, etc.).However, laboratory investigations of various completely different aspects of the processes of cancer induction (viruses, mutagens, host control mechanisms, etc.) are already well established, and new lines of investigation, particularly of "cocarcinogenic" processes, may yet emerge. No single process is likely to be the whole truth, and we must hope that some grand synthesis of the known processes will eventually be put together which will describe all the essential features of human cancer induction. Although the eventual synthesis is not yet in sight, multistage models should at present be thought about to some extent, and their general features should be common knowledge, as the general framework of this eventual synthesis will (at least for that 90% of fatal human cancers which are carcinomas) almost certainly be some kind of multistage model. Moreover, despite all their present uncertainties, multistage models for carcinoma induction have already offered plausible answers to various questions concerning monoclonality, dose-response relationships under conditions of regular exposure, hypothetical "threshold" doses, the synergistic effects of different carcinogens, the role of luck, and, last but not least, the connection between cancer and aging. (This latter point has been only partly resolved: multistage models give a very natural explanation for cancer being a hundred times rarer among young adults than among the elderly, but no plausible explanation has yet been offered for the fact that the risk of cancer in old age is not vastly different in species with very different life-spans.)In the next three sections, I will recapitulate a few formulae that can emerge from certain multistage models.(Readers who don't like even simple algebra can pass over

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Section: Disparity Between the Exponents Of Dose And Timementioning

confidence: 99%

Epidemiology, multistage models, and short-term mutagenicity tests

Pető¹

2016

Int. J. Epidemiol.

100

107

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“…Lee et al (1977) have shown that virtually all the carcinogenic components of whole-smoke condensate are insoluble in water. Davies et al (1974) demonstrated that the use of a hydrophobic alcohol (isopropyl alcohol) as a solvent for condensate increased the incidence of tumours over that achieved with the usual solvents.…”

Section: Discussionmentioning

confidence: 99%

Effect of glycerol on local and systemic carcinogenicity of topically applied tobacco condensate

Wilson¹,

Clapp²,

Conning³

1978

Br J Cancer

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Summary.-When glycerol was added to tobacco smoke condensate in acetone solvent, the topical carcinogenicity and the ability to produce epithelial hyperplasia in mice was reduced. Two doses of condensate were applied, combined with 2 concentrations of added glycerol. Age-standardized results show that glycerol reduced the incidence of tumours and malignant tumours and of hyperplasia in animals not developing skin tumours. The relative incidences of malignant tumours, benign tumours, hyperplasia and unaffected skin suggest that there is a sequential relationship (i.e. normal skin to hyperplasia to benign neoplasia to malignant neoplasia) which is impeded by glycerol. There was no systemic effect attributable to the condensate.IN STUDIES on the carcinogenicity of smoke condensate of tobacco and NSM* it was noted that NSM condensates showed less than 250% of the tumour-producing activity of tobacco (Clapp et al., 1977). This was attributed to the general reduction of the particulate-phase activity of NSM smoke, but comment was made that the substantial carry-over into smoke of the humectant used (glycerol) might have been a factor of significance. Glycerol constitutes between 40%0 and 50°/ of the particulate phase of NSM smoke and it seemed possible that this amount might influence the response of mouse skin to the carcinogenic effect of smoke condensate, quite apart from any effect of the dilution of carcinogenic constituents. The experiment described here was designed to determine whether the presence ofglycerol, as a diluent of tobacco condensate, itself influenced the carcinogenicity of the condensate irrespective of an effect on dosage.

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“…The results of the first experiment indicated that Fraction (R + P)G, which 3-3 (6) 0.0 (7) 00 (6) 0 0 (6) 0 * 3 (6) 0-1 (11) 15-2 (13) 6-1 (12) 2 -9 (9) 1-0 (1) 0.-4 (17) 0-2 (10) forms only 3.5O% of whole-smoke condensate and is almost as tumorigenic for mouse skin as the much larger mass of whole-smoke condensate from which it is derived (Lee et al, 1977) pigment (GBM) and foci of cuboidal/ columnar metaplasia ofalveolar epithelium (CCM). This increase was time-related but apparently irrespective of dose, although the apparent lack of dose response may have been due to the response being maximal at the lowest dose studied.…”

Section: Discussionmentioning

confidence: 99%

“…In the case of mouse skin, there is evidence that the tumorigenic activity of Fractions (R + P)G from different smoke condensates parallel the activities of the smoke condensates from which they are derived (Lee et al, 1977). If this is as true for rat lung as for mouse skin, tests on rat lung of Fraction (R + P)G from different condensates might be useful for comparing the overall tumorigenicity of different condensates.…”

Section: Discussionmentioning

confidence: 99%

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Squamous Lesions in the Lungs of Rats Exposed to Tobacco-smoke-condensate Fractions by Repeated Intratracheal Instillation

Simons¹,

P²,

Roe³

1978

Br J Cancer

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Summary.-Twice-weekly intratracheal instillations in rats of up to 24 mg of Fraction (R + P)G suspended in either infusine (I) or buffered saline/gelatine (BS/G) gave rise to foci of squamous metaplasia of alveolar epithelium (SqM) and squamous neoplasms (SqN). Fraction (R + P)G, which is a fraction of cigarettesmoke condensate almost as tumorigenic for mouse skin as the nearly 30 x larger mass of condensate from which it is derived, could be given in this way for up to 40 weeks without excessive mortality or any marked effect on the rate of body-weight gain. By contrast, similar treatment with Fraction N(QG), a fraction having very low tumorigenic activity for mouse skin, induced no SqN and barely any excess of SqM over that induced by either vehicle alone.The effects of Fraction (R + P)G on the incidence of SqM and SqN were both time and dose related, the effect on SqM incidence being already evident after 10 weeks of treatment. No SqN seen were unequivocally malignant, though, due to the design of the experiment, only 5 rats exposed to Fraction (R + P)G were observed more than 60 weeks after the start of the experiment.Other changes in the lung, including aggregates of alveolar macrophages laden with golden-brown pigment (GBM) and foci of cuboidal/columnar metaplasia of alveolar epithelium (CCM), were frequently seen in response to both fractions. Fraction (R + P)G administered in I was more effective in causing SqM and SqN than the same fraction administered in BS/G. The implications of the findings are discussed, particularly the possibility that the intratracheal/instillation technique might be useful as a rapid bioassay for comparing the tumorigenicity of different cigarette-smoke condensates.

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Fractionation of mouse skin carcinogens in cigarette smoke condensate

Cited by 11 publications

References 9 publications

Epidemiology, multistage models, and short-term mutagenicity tests

Epidemiology, multistage models, and short-term mutagenicity tests

Effect of glycerol on local and systemic carcinogenicity of topically applied tobacco condensate

Squamous Lesions in the Lungs of Rats Exposed to Tobacco-smoke-condensate Fractions by Repeated Intratracheal Instillation

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