The Bystander Effect and a Supralinear Dose-Response Curve

Hall (2003) “The Bystander Effect,” Health Physics, 85:31–35.

When discussing the biological effects of radiation in Intermediate Physics for Medicine and Biology, Russ Hobbie and I describe the bystander effect.

Ionization damage is not the entire story. The bystander effect in radiobiology refers to the “induction of biological effects in cells that are not directly traversed by a charged particle, but are in close proximity to cells that are” (Hall 2003; Hall and Giaccia 2012).

I sometimes reread the references we cite, looking for interesting tidbits to share in this blog. Below is the abstract to the 2003 article by Eric Hall about the bystander effect (Health Physics, Vol. 85, Pages 31–35).

The bystander effect refers to the induction of biological effects in cells that are not directly traversed by a charged particle. The data available concerning the bystander effect fall into two quite separate categories, and it is not certain that the two groups of experiments are addressing the same phenomenon. First, there are experiments involving the transfer of medium from irradiated cells, which results in a biological effect in unirradiated cells. Second, there is the use of sophisticated single particle microbeams, which allow specific cells to be irradiated and biological effects studied in their neighbors; in this case communication is by gap junction. Medium transfer experiments have shown a bystander effect for cell lethality, chromosomal aberrations and cell cycle delay. The type of cell, epithelial vs. fibroblast, appears to be important. Experiments suggest that the effect is due to a molecule secreted by irradiated cells, which is capable of transferring damage to distant cells. Use of a single microbeam has allowed the demonstration of a bystander effect for chromosomal aberrations, cell lethality, mutation, and oncogenic transformation. When cells are in close contact, allowing gap junction communication, the bystander effect is a much larger magnitude than the phenomenon demonstrated in medium transfer experiments. A bystander effect has been demonstrated for both high- and low-LET radiations but it is usually larger for densely ionizing radiation such as alpha particles. Experiments have not yet been devised to demonstrate a comparable bystander effect on a three-dimensional normal tissue. Bystander studies imply that the target for the biological effects of radiation is larger than the cell and this could make a simple linear extrapolation of radiation risks from high to low doses of questionable validity.

Our discussion of the bystander effect in IPMB closely parallels that given by Hall. But in his article Hall wrote this

This bystander effect can be induced by radiation doses as low as 0.25 mGy and is not significantly increased up to doses of 10 Gy

and this

When 10% of the cells on a dish are exposed to two or more alpha particles, the resulting frequency of induced oncogenic transformation is indistinguishable from that when all the cells on the dish are exposed to the same number of alpha particles.

What?!? The bystander effect is not increased when the dose increases by a factor of forty thousand? You can fire three alpha particles per cell at only one out of every ten cells and the response is the same as if you fire three alpha particles per cell at every cell? I don’t understand.

Another surprising feature of the data is that all these changes are different than they are for zero dose. That means the dose-response curve must start at zero, jump up to a significant level, and then be nearly flat. Such a dose-response behavior is different than that predicted by the linear no-threshold model (linearly extrapolating from what is known about radiation risk at high doses down to low doses). Indeed, that is what Hall is hinting at in the last sentence of his abstract.

Below is a slightly modified version of Figure 16.51 from IPMB. It shows different assumptions for how tissue responds to a dose of radiation. Data exists (the data points with error bars) for moderate doses, but what happens at very low doses? The standard dogma is the linear no-threshold model (LNT), which is a linear extrapolation from the data at moderate doses down to zero. Some believe there is a threshold below which low doses of radiation have no effect, and a few researchers even claim that very low doses can be beneficial ( hormesis). Hall’s hypothesis is that the bystander effect would have a larger impact at low doses than predicted by the linear no-threshold model. It would be a supralinear effect. Based on Fig. 6 of Hall’s article, the effect would be dramatic, like the red bystander curve I added to our figure below.

Possible responses of tissue to various doses of radiation. The two lowest-dose
measurements are shown. With zero dose there is no excess effect.
Adapted from Fig. 16.51 of Intermediate Physics for Medicine and Biology.

Previously in this blog, I have expressed skepticism of the linear no-threshold model, leaning more toward a threshold model in which very low doses have little or no effect. Hall’s claim implies the opposite: very low doses would have a bigger effect than expected from the linear no-threshold model. What do I make of this? First, let me say that I’m speculating in a field that’s outside my area of expertise; I’m not a radiation biologist. But to me, it seems odd to say that zapping 10% of the cells with alpha particles will have the same effect as zapping 100% of the cells with alpha particles. And it sounds strange to say that the response is not significantly affected by increasing the dose by a factor of 40,000. I don’t usually ask for assistance from my readers, but if anyone out there has an explanation for how this dramatic supralinear effect works, I would appreciate hearing it.

One of the most important questions raised in IPMB is: What is the true risk from low doses of radiation. The bystander effect is one factor that goes into answering this question. We need to understand it better.

The career of Eric Hall. https://www.youtube.com/watch?v=eh6erz_Ds0M

Originally published at http://hobbieroth.blogspot.com.

Professor of Physics at Oakland University and coauthor of the textbook Intermediate Physics for Medicine and Biology.