Overview of Results
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 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]
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]
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]
Partial Body Irradiations
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:
Exposures 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.