A Mechanistic Model for Neoplastic Transformation of Cells by High-LET Radiation and its Implications for Low-Dose, Low-Dose Rate, Risk Assessment

Abstract

A current trend in low dose, low dose rate, risk assessment is the use of mechanistic models. In vitro neoplastic transformation studies have demonstrated that protracted exposure of cells to low doses of high LET radiation can lead to more transformants per survivor than the same dose delivered at a high rate. This phenomenon is called an inverse dose rate effect. Researchers have developed biophysical models to characterise the in vitro inverse dose rate effect for neoplastic transformation by high LET radiation, and some have claimed that their models also explain the inverse dose rate effect for lung cancer induction observed in miners exposed to alpha radiation from radon daughters. A new mechanistic biomathematical model called NEOTRANS, (pronounced 'neotrans one') is presented to explain the inverse dose rate effect for neoplastic transformation in vitro; however, results of its application support the view that the inverse dose rate effect seen in vitro may be unrelated to that demonstrated for the induction of lung cancer in miners. NEOTRANS 1 is a genomic instability state (GIST) model. GIST models can be developed on the premise that differing states of genomic instability arise in mammalian cells from radiation-induced DNA damage, and genomic instability can lead to various outcomes, including gene-regulated arrest at cell cycle checkpoints (e.g. to reduce transient genomic instability via facilitating efficient DNA repair); apoptosis (a form of programmed cell death which selectively eliminates cells with problematic genomic instability); and neoplastic transformation (which arises spontaneously because of persistent, problematic, genomic instability carried by progeny of irradiated cells). Like GIST models in general, NEOTRANS 1 is kinetic and includes effects of genomic damage accumulation, DNA repair during cell cycle arrest, DNA misrepair (e.g. non-lethal repair errors), and spontaneous transformation of daughter cells with persistent problematic genomic instability. Cell killing and neoplastic transformation in vitro are treated as being statistically independent (i.e. not correlated over the cell population at risk) when cells are exposed to high LET radiation. With NEOTRANS 1 , the inverse dose rate effect for neoplastic transformation is attributed to genomic instability arising from DNA repair errors associated with a postulated fast, error-prone repair process (repair half-time≃4 min) operating in a hypersensitive subset of cells. NEOTRANS 1 is shown to account for key experimental observations obtained in vitro following exposure of C3H 10T1/2 cells to high LET radiations (neutrons or alpha particles), including the neutron inverse dose rate effect and the complex dose-response curve observed after exposure at high dose rates. Because the inverse dose rate effect is explained based on genomic instability arising from errors associated with a fast repair process, it is concluded that the inverse dose rate effect observed in vitro at relatively high dose rates (0.1 to 100 mGy.min -1 ) is probably unrelated to that observed for the induction of lung cancer in miners exposed via inhalation, over years, to alpha radiation at very low average dose-rates. It is suggested that age-related changes in the lung (e.g. an increase in genomic instability with age due to a decline in DNA repair efficiency associated with aging) could be responsible for the inverse dose rate effect seen in miners exposed to radon daughters.