Abstract
The multistage model is currently a widely used mathematical tool in carcinogen risk assessment to obtain a low-dose linear non-threshold slope for estimating cancer risks and comparing carcinogens with respect to potency. However, the multistage model is a single pathway model, whereas biological evidence indicates that carcinogenesis proceeds through multiple pathways. Furthermore, recent studies suggest that carcinogens induce a generalized increase in the susceptibility to neoplastic transformation triggered as rare events by cell proliferation. Such evidence supports the dtn = c time to tumor model in a modified form.
When assessment of carcinogenic chemicals was begun by the Carcinogen Assessment Group (CAG) at the U.S. Environmental Protection Agency in 1976, the use of low-level non-threshold linear extrapolation was taken over from the field of ionizing radiation on the basis of the mechanistic linkage between carcinogenesis and mutagenesis, the linearity of dose-response for mutagenesis, and the consistency with linearity of at least some epidemiological dose-response data for cancer1. Additional arguments were added in support of low-dose linearity for chemicals: non-threshold dose-response linearity for tumor initiation2 and virtual low-dose linearity when the mode of action of the agent in question and the background causes are the same; as indicated below, this is inherent in the multistage model of carcinogenesis.
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Albert, R.E. (1986). The Time to Tumor Approach in Risk Assessment. In: Simic, M.G., Grossman, L., Upton, A.C., Bergtold, D.S. (eds) Mechanisms of DNA Damage and Repair. Basic Life Sciences, vol 189. Springer, Boston, MA. https://doi.org/10.1007/978-1-4615-9462-8_58
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DOI: https://doi.org/10.1007/978-1-4615-9462-8_58
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