A two-mutation model of radiation carcinogenesis: application to lung tumours in rodents and implications for risk evaluation

Abstract

An attempt is made to develop a model for radiation carcinogenesis linking DNA damage to malignancy. A modification of the two-stage model for carcinogenesis developed by Knudson and Moolgavkar (see J. Natl. Acad. Sci. (USA), vol. 68, p. 1037-52, 1981) is combined with a linear-quadratic dose response model for cellular radiation effects to analyse radiation induced lung tumours in rodents for a variety of radiation types and conditions. The combined model provides the possibility of calculating the age dependent and dose dependent incidence of cancer simultaneously and is used to fit data of lung tumours in mice and rats exposed to different radiation types. The satisfactory application of the combined model to animal data has led to an examination of the implications of the model, which may prove to be far-reaching for the extrapolation of risk to low doses, the effect of life exposures and other aspects of radiation risk assessment.

Analysis of thyroid cancer data from the Ukraine after ’Chernobyl' using a two-mutation carcinogenesis model

“…The model used to fit the data is the two-mutation model with clonal expansion, as described by Leenhouts and Chadwick [18]. A schematic representation is given in Fig.…”

“…This carcinogenesis process proceeds naturally with background mutation and expansion rates dependent on the organ. In applying this model to experimental animal and epidemiological data, it has been assumed that external factors, such as radiation, can change the mutation rates, causing increased tumour probability [18,19]. This is due to the mutation effect of ionizing radiation, well established from cellular radiation biology.…”

“…These models have been successful in fitting the increase in spontaneous cancer incidence with age and have also been used to analyse several sets of epidemiological data after radiation exposure [10,11,12,13,14,15,16,17]. In this field, Leenhouts and Chadwick [18] developed a two-mutation carcinogenesis model to analyse radiation-induced cancer and particularly to link the action of radiation at the cellular level with cancer induction. The analysis of several radiation-induced animal tumour systems and epidemiological data has resulted in conclusions about the radiation action in cancer development.…”

“…For example, ionizing radiation is thought to act in general as an initiating agent, i.e. the first mutation step of the model is dependent on radiation [18,19]. However, for other animal tumours with a relatively rare background or spontaneous prevalence, a good fit has been achieved with radiation dependence on both mutation steps [20,21].…”

Multistage carcinogenesis modeling and the initiation event

“…Previously we have published [1] a modified version of the two-mutation model of carcinogenesis developed by Moolgavkar and Knudson [2], schematically represented in Figure 1, and discussed some of its implications for radiological protection.…”