AT and XR-V15B cell lines (Skov 1999) or with high-LET radiation (Lambin and others 1993). For doses above 50–200 mGy, for which HRS is no longer observed, the flattening of the survival curve between 500 and 1000 mGy may be related to DNA PKcs activity (Marples and others 2002) or to the downregulation of the DIR1 gene (Robson and others 1997, 1999); this downregulation has been shown to correlate with an increase in rate of repair of DNA single-strand breaks (Robson and others 2000; Collis and others 2004; Marples and others 2004).
DNA damage introduced at a very low rate may not activate the radiation damage sensor ATM (Collis and others 2004). Consequently, exposure to low levels of chronic radiation may cause more cell damage than estimated from extrapolation of higher doses. This hypersensitivity to killing could serve to eliminate cells that have received DNA damage and potentially carcinogenic changes to their genome. Alternatively, it cannot presently be excluded that some of these cells may survive and proliferate as clones of mutated cells. It is important to note that the effect of cellular hypersensitivity to killing by very low chronic doses of ionizing radiation is a modest effect that has been detected only in some, but not all, human cell lines investigated.
Studies of other end points have provided some additional evidence of HRS. In a signal transduction study that used γ-ray doses of 20, 50, 100, 250, and 500 mGy, there was a suggestion of HRS up to 200 mGy for radiation-induced transcription of MDM2, ATF3, and BAX in a human myeloid tumor line (Amundson and others 1999b; Figure 2-4).
Similar observations over the same dose range were reported (Yang and others 2000) for X-ray induction of protein-8 (XIP8) in human MCF-7:W58 breast cancer cells; this protein as it complexes with Ku70/Ku80 appears to be an important cell-death signal. HRS was also observed in mice as gene deletions that reverted unstable mutations in melanocytes exposed to 10 mGy of X-radiation (Schiestl and others 1994); that is, there was a threefold effect at 10 mGy and a twelvefold effect at 1 Gy. The frequency of gene deletions was about 100 times higher than the frequency of other