We have performed groundbreaking studies on the response of various biomarkers to complex irradiation fields, concentrating on dose rate effects, partial body exposures, internal emitters, and neutrons. Additionally, we have investigated the use of our biomarkers (micronuclei and DNA repair kinetics) as predictive assays of acute radiation sequelae in both mouse and man.
Dose rate effects
For Micronuclei yields, we have seen that Low dose rate (LDR) X-rays generated inherently linear dose-response curves, whereas acute exposure has a strong quadratic component. This is explained by the fact that at the lower dose rate, DNA breaks may have time to repair before the next x-ray interacts with that cell, whereas the acute dose may cause the formation of more micronuclei due to the interaction of effects from “consecutive” x-rays hitting the same cell. At the acute dose rate, this time is much shorter and repair cannot occur. Subsequently, the dose-response curve contains a quadratic element stemming from two x-ray effects.
Bertucci A, Smilenov LB, Turner HC, Amundson SA, Brenner DJ. In vitro RABiT measurement of dose rate effects on radiation induction of micronuclei in human peripheral blood lymphocytes. Radiat Environ Biophys 55(1):53-9 (2016) [PMC] [Journal]
Turner HC, Shuryak I, Taveras M, Bertucci A, Perrier JR, Chen C, Elliston CD, Johnson GW, Smilenov LB, Amundson SA and Brenner DJ. Effect of dose rate on residual γ-H2AX levels and frequency of micronuclei in X-irradiated mouse lymphocytes. Rad Res 183(3):315-324 (2015) [PMC] [Journal]
We have performed internal emitter irradiations of mice using both 137Cs and 90Sr.
A mechanistic mathematical model (solid line in the figure) was applied to the data and successfully predicted the initial decline in the γ-H2AX frequency (due to the death of differentiated mature lymphocyte cells), as well as the increase in γ-H2AX frequency observed between Day 5 and 30, is due to the production of new lymphocytes from damaged progenitor cells.
Similarly, the model successfully predicted the γ-H2AX yields from internalized 90Sr, which has a very different dose profile.
Turner HC, Shuryak I, Weber W, Doyle-Eisele M, Melo D, Guilmette R, Amundson SA, Brenner DJ. γ-H2AX Kinetic Profile in Mouse Lymphocytes Exposed to the Internal Emitters Cesium-137 and Strontium-90. PLoS ONE 10(11):e0143815 (2015) [PMC] [Journal]
Partial Body Irradiations
We have studied samples obtained from partial body irradiations and were able to reconstruct the dose and fraction of body irradiated. At 3 days post-irradiation, micronuclei yields in mononuclear cells were significantly elevated when compared to time-matched controls with a clear dose dependence. In addition, there seems to be a difference in frequencies depending on which region of the body was irradiated, with lower body irradiations producing higher micronuclei frequencies than upper body irradiations at similar doses. The figure demonstrates our Contaminated Poisson algorithm for dose reconstruction from γ-H2AX measurements. The Black and Green curves respectively show a Poisson fit to the γ-H2AX fluorescence frequency in mice irradiated to 0 and 6 Gy respectively. The blue curve is a double Poisson fit generated for a mouse in which only the upper body was irradiated to 6 Gy. This clearly shows that about 30% of the blood was irradiated to 6 Gy with the rest unirradiated.
Using our novel IND-like neutron irradiator we have irradiated human blood samples as well as mice with Neutrons and mixed neutron/photon fields. As expected, the results show that the response to neutron irradiation is significantly higher than to an equal dose of X-rays. RBE values for the various RABiT endpoints are:
|mBAND||6Exposures are expected to be primarily photons with a small fraction (by dose) of neutrons. However, due to the high RBE values of neutrons, the biological effects of even a small neutron exposure may match or exceed those of the photon dose. We have therefore started investigating dose reconstruction in mixed neutron/photon fields.|
The figure shows, for example, micronucleus yields in a mixed photon neutron exposure.