observed when cell culture medium from irradiated cells was added to nonirradiated cells (Mothersill and Seymour 1998a). The observed bystander effect is specific for keratinocytes because it was not observed for fibroblasts. The effect is eliminated by heating the medium at 70°C for 30 min, and there is some evidence that an alteration in energy metabolism and induction of apoptosis are involved (Mothersill and others 2000b). Furthermore, the bystander effect from transfer of medium varies among cell lines (Mothersill and others 2000b; Seymour and Mothersill 2000), and its contribution to cell lethality has been reported either to plateau with about 40% of human keratinocytes killed at 30–60 mGy (Seymour and Mothersill 2000) or to increase at doses over 1 Gy delivered to CHO (Chinese hamster ovary) cells (Mothersill and others 2000b). Finally, bystander cell killing reported for a dose as low as 10 mGy appears to be greater for delayed cell lethality quantified by cloning efficiency at about 14 d after irradiation than for initial cell lethality quantified by cloning efficiency determined immediately after irradiation (Seymour and Mothersill 2000). Delayed lethality is supposedly a manifestation of genomic instability associated with an increase in lethal mutations in cells that survive irradiation (Seymour and Mothersill 1997).

In another study, a low-LET radiation bystander effect that required gap junctions was observed in a three-dimensional Chinese hamster culture model (Bishayee and others 1999). The bystander effect that caused cell lethality in the nonirradiated cells became apparent only after the irradiated cells had undergone 1000–2000 disintegrations of 3HTdR in the DNA, that is, at a very high dose of about 2.5–5.0 Gy (Dewey and others 1965).

Several issues should be considered in relation to the bystander effect. First, in contrast with the results summarized above that involved enhancement of damage, a bystander effect was reported to increase survival (Dent and others 1999) when medium from γ-irradiated mammary carcinoma cells was transferred to nonirradiated cells 120 min after a dose of 2 Gy. Apparently, the soluble TGF-α (transforming growth factor-α) that was released induced secondary activation of EGFR (epidermal growth factor receptor), MAPK (mitogen-activated protein kinase), and JNK (c-jun N-terminal kinase), which resulted in an increase in survival. Thus, as reviewed by Waldren (2004) both beneficial and detrimental effects may result from the bystander effect. A similar observation was reported for normal human diploid lung fibroblasts exposed to low doses of α-particles; the observed enhancement of cell growth was hypothesized to result from an ROS-caused increase in TGF-β (Iyer and Lehnert 2000). Second, there is a suggestion that an adaptive response induced by a priming dose of 1 mGy for reducing radiation-induced micronuclei was due in part to a bystander effect (Broome and others 2002). However, the bystander effect of a priming dose has not been found to induce a radioprotective or adaptive response for chromosomal aberrations or cell killing (Wolff 1992b; Mothersill and Seymour 1998a). Third, an adaptive response induced by irradiating a cell directly may cancel out at least part of the bystander effect; this was observed for cell lethality when mouse C3H 10T1/2 cells were irradiated with 20 mGy of X-rays 6 h before α-particle irradiation (Sawant and others 2001b). Fourth, molecular mechanisms responsible for the bystander effect of low-LET radiation, as well as high-LET radiation, that may include genetic variation in transcriptional response to radiation exposure (Correa and Cheung 2004), have not been delineated. Fifth, recent results (Prise and others 2003) suggest that a bystander effect for cell lethality from soft X-ray irradiation (LET of 25–30 keV/μ) might be observed down to 50 mGy but not below. Sixth, until molecular mechanisms of the bystander effect are elucidated, especially as related to an intact organism, and until reproducible bystander effects are observed for low-LET radiation in the dose range of 1–5 mGy, where an average of about one electron track traverses the nucleus, a bystander effect of low-dose, low-LET radiation that might result in a dose-response curving either upwards or downwards should not be assumed.


Another factor that can cause the dose-response to deviate from the alpha-beta model is HRS that has been reported for cell lethality induced by low-LET radiation at doses up to 200 mGy (Joiner and others 1996; Skov 1999; Figure 2-3). In this dose range, survival can decrease to 85–90%, depending on the cell line, which is significantly lower than survival predicted by the value of α determined from survival values above 1–2 Gy. HRS might be associated with a bystander effect, but a recent study (Mothersill and others 2002) suggests that it is not. Although the magnitude of HRS varies, there is some evidence that it also occurs for fractionated doses of about 400 or 500 mGy both in vitro (Smith and others 1999; Short and others 2001) and in vivo for kidney and skin (Joiner and others 1996) and for glioma cell lines irradiated with multiple fractions of 700–800 mGy (Beauchesne and others 2003). Furthermore, an observed inverse dose-rate effect was attributed to HRS seen for low acute doses (Mitchell and others 2002), and recent cell cycle studies (Mitchell and others 2002; Marples and others 2003; Short and others 2003) suggest that HRS may be related to cells not arresting in radiosensitive G2. Since a high proportion of the target stem-like cells in humans would be noncycling G0 cells (see Chapter 3, “General Aspects of Dose-Response”), the last two observations, if generally true, would suggest that neither HRS nor the inverse dose-rate phenomenon should have any significant effect on the dose-response for cancer induction in humans.

Molecular mechanisms involved in HRS have been described in only a preliminary way. However, HRS for cell lethality up to 200 mGy was not observed in radiosensitive

The National Academies of Sciences, Engineering, and Medicine
500 Fifth St. N.W. | Washington, D.C. 20001

Copyright © National Academy of Sciences. All rights reserved.
Terms of Use and Privacy Statement