Multistage model of carcinogenesis

FIGURE 124-2. Multistage model of carcinogenesis. (Adapted with permission from Weston et al. )... 

A model that attracted much attention was one that attempted to account for the multistage hypothesis of carcinogenesis, discussed in... 

Little, M. P. (1995). Are two mutations sufficient to cause cancer Some generalizations of the two-mutation model of carcinogenesis of Moolgavkar, Venzon, and Knudson, and of the multistage model of Armitage and Doll. Biometrics 51, 1278-1291. 

Adult 0.15-0.37 Estimated dietary exposure Baffin Island male Inult 11 The 11 pg/kg bw/d was derived using a safety factor of 1,000 applied to a value of 11 mg/kg body weight, based on multistage modeling of tumors with the highest incidence in the carcinogenesis bioassay of male mice that resulted in 5% increase in tumor incidence [1, 21]... 

Figure 24.27. Mouse skin model of multistage carcinogenesis. Genetic changes associated with mouse skin tumorigenesis.

For the above reasons, the linearized multistage model is used as a default when estimating risks for short-term exposures from lifetime carcinogenesis bioassays. In all of the above referenced publications on the multistage model, the maximum number of stages modeled was six. 

Yeh CN, Maitra A, Lee KF, Jan YY, and Chen MF (2004) Thioacetamide-induced intestinal-type cholangiocarcinoma in rat An animal model recapitulating the multistage progression of human cholangiocarcinoma. Carcinogenesis 25 631-636. 

Rotstein JB, Slaga TJ. 1988. Acetic acid, a potent agent of tumor progression in the multistage mouse skin model forchemical carcinogenesis. Cancer Lett. 42 87-90... 

CTAs are possible in vitro alternatives to the standard approach for the assessment of carcinogenicity (the 2-year bioassay in rodents), which have been shown to be a multistage process able to model the most important stages of in vivo carcinogenesis [50]. CTAs are faster and more economic than in vivo assay and they could be a valid and useful screening tool for chemicals. 

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