A mechanistic model for neoplastic transformation of cells by high LET radiation and its implications for low dose, low dose rate, risk assessment

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 NEOTRANS1 (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. NEOTRANS1 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 redce 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). (Author)