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Radiation-Induced Bystander Effects and Relevance to Human Radiation Exposures Review of phenomenon appears in Radiation Research

One concern of radiobiologists is the effect radiation exposure might have on nearby unirradiated cells. For example, when only a small fraction of cells are directly hit by radiation energy, are the surrounding unirradiated cells also at an increased risk of cancer? The term "radiation-induced bystander effect" is used to describe radiation-induced biological changes that occur in unirradiated cells within an irradiated cell population.

Radiation-induced bystander effects have become established in the vernacular and are considered as an authentic radiation response. However, there is still no consensus on a precise definition of the term, which currently encompasses a number of distinct signal-mediated effects. In a review recently published by Low Dose Program investigators Benjamin Blyth and Pamela Sykes, Flinders University, Australia, these effects have been given three classifications: bystander effects, abscopal effects, and cohort effects (see figure).

Results. In the review paper, published in the August 2011 issue of Radiation Research, the authors evaluated data to define various features specific to radiation-induced bystander effects. These features include timing, range, potency and dependence on dose, dose rate, radiation quality and cell type. They discussed the weight of evidence supporting these features in the context of bystander experimental systems that closely replicate realistic human exposure scenarios.

Top: Bystander effects are communicated between irradiated cells and nearby unirradiated cells within the irradiated volume.              

Middle: Abscopal effects are communicated between irradiated tissues and unirradiated tissues outside of the irradiated volume, either directly or via systemic signaling.          

Bottom: Cohort effects occur between irradiated cells within an irradiated volume. Adapted from Blyth BJ and PJ Sykes. 2011. Radiation Research 176(2):139-157

"First, scientists must clarify the boundaries of what a bystander effect is and what it is not," states Blyth. "Only by following a systematic definition of the term can we accurately characterize the phenomenon."

They considered whether the manifestation of bystander effects in vivo is intrinsically limited to particular radiation exposure scenarios. According to Sykes, "The conditions under which radiation-induced bystander effects are induced in vivo will ultimately determine their impact on radiation-induced cancer risk."

Methods. The authors compared 12 definitions of bystander effects from published scientific articles. Of these, six made no reference to the location of the unirradiated cells or any limitations on distance from irradiated cells; four explicitly restricted bystander cells to nearby, proximal, or neighboring cells; and the remaining two explicitly included nearby and distant locations. In response, the authors proposed the three classes of signal-mediated effects. The evidence supporting the nature and relevance of bystander effects in vivo was then reviewed in light of this proposed definition.

Conclusions. Blyth and Sykes suggest that despite the wide variety of biological end points, experimental systems, and types of signal-mediated effects reported in the literature, the data are often discussed as a whole and presented as collective evidence supporting bystander effects. However, the wealth of data should not be mistaken for overwhelming evidence of a singular, generic bystander effect. They warn that combining the diverse biological outcomes into a single effect can give the false impression that observation of "the bystander effect" has been universal.

They also suggest that some of the discrepancy found in the literature can be attributed to genuine disagreement over the definition of bystander effects, but much of the discord is historical and is tied to the limitations of different experimental techniques. Says Blyth, "With each new experimental observation, even in cells that clearly fall outside the scope of bystanders, the meaning of the term ‘bystander effect' has been expanded."

The authors also argue that for each experiment, it is crucial to consider the biological effects that were anticipated but were not observed in bystander cells, despite being routinely observed in other systems. The end points that do not change in any particular system should be regarded with the same or greater interest than those that do.

The current data on bystander effects, as defined in this review, suggest that the final biological outcome in bystander cells is dependent on a wide variety of factors including dose, dose rate, radiation quality and cell/tissue type. This complexity means that although much is known about bystander effects, the relevance of bystander effects to carcinogenic risk cannot yet be determined.

Reference: Blyth BJ and PJ Sykes. 2011. "Radiation-Induced Bystander Effects: What Are They, and How Relevant Are They to Human Radiation Exposures?" Radiation Research 176(2):139-157. doi: 10.1667/RR2548.

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