Page 356 - 2014 Printable Abstract Book
P. 356
Methods: Thirty-two male Gottingen minipigs, approximately 5 months old, weight 9-11 kg, were
irradiated bilaterally using gamma irradiation (total body, Co-60, 0.6 Gy/min) in the dose range 5-12 Gy.
Following exposure, the animals were evaluated for up to 10 days through observation of clinical signs,
CBC counts and parameters associated with the development of the GI syndrome (including vomiting,
diarrhea, bacteria translocation, loss of crypts, shortening of villi, and decline in plasma citrulline).
Results and conclusion: A dose-dependent occurrence of all classical parameters associated with acute
GI-ARS occurs in the Gottingen minipig exposed to gamma radiation in the dose range between 5 and 12
Gy. These results suggest the Gottingen minipig may a suitable model to study GI-ARS. Knowledge of the
natural history as well as a determination of reliable endpoints for the different ARS sequelae, is required
for drug testing. This study is the first step toward determing such requirements and towards evaluating
the feasibility of using the Gottingen minipig for drug efficacy testing to treat the GI-ARS. Additional
studies are necessary to bracket radiation doses causing the GI syndrome in this model and to confirm
validity of endpoints for euthanasia. The views expressed here do not necessarily represent the Armed
Forces Radiobiology Research Institute, the Uniformed Services University of the Health Sciences, or the
Department of Defense.
(PS7-5) Estimating radiation risk by measuring chromosomal rearrangements occurring in pKZ1 mice
1
1
following acute and chronic low-dose radiation exposures. Laura Bannister ; Mandy Serran ; Rebecca
1
1
1
2
Mantha ; Lyndsey Duck ; and Pamela Sykes , Atomic Energy Canada Limited, Chalk River, Canada and
Flinders Medical University, Adelaide, Australia
2
pKZ1 mice contain a transgene allowing quantification of chromosomal DNA inversion events in
vivo arising spontaneously or in response to genotoxic reagents. DNA repair mediated inversion of the
transgene can be considered as a surrogate risk marker for genomic rearrangements associated with
radiation-induced carcinogenesis. The pKZ1 assay is extremely sensitive, with changes in transgene
inversion frequency occurring at doses of ionizing radiation and other mutagens that are orders of
magnitude lower than those eliciting responses in studies using alternate rodent models. The pKZ1 mouse
model is currently being utilized at AECL for two collaborative research projects that examine the effects
of low-LET ionizing radiation, using doses and dose rates that are relevant to environmental, occupational
and medical exposures. One project addresses the true shape of stochastic endpoint dose response curves
at low doses below which the epidemiological risk for cancer induction remains uncertain. Dose response
curves for pKZ1 inversions in spleen and prostate following total body X-ray irradiation do not conform to
Linear-No-Threshold (LNT) expectation of Radiation Protection, indicating that non-targeted effects are
playing an important role at low radiation doses. The aim of this first project is to generate a low-LET
60
splenic pKZ1 dose response curve using Co gamma radiation (mean photon energy 1.25 MeV) for
comparison with previous results obtained with 250kV X-Rays, spanning a dose range 0.01 mGy to 2 Gy
and using doses and dose rates similar to those used in X-Ray irradiation experiments. The second project
compares the biological effects of chronic low-dose tritium exposure for one month or eight months to
equivalent doses of gamma radiation, using doses and dose rates that are relevant to regulatory levels for
tritium in drinking water (10 kBq/L, 1 MBq/L and 20 MBq/L). This project was undertaken to investigate
the health effects of tritium exposures and, in particular, uncertainty concerning the reliability of the
currently used ICRP recommended radiation weighting factor (WR) of 1 for the calculation of committed
354 | P a g e
irradiated bilaterally using gamma irradiation (total body, Co-60, 0.6 Gy/min) in the dose range 5-12 Gy.
Following exposure, the animals were evaluated for up to 10 days through observation of clinical signs,
CBC counts and parameters associated with the development of the GI syndrome (including vomiting,
diarrhea, bacteria translocation, loss of crypts, shortening of villi, and decline in plasma citrulline).
Results and conclusion: A dose-dependent occurrence of all classical parameters associated with acute
GI-ARS occurs in the Gottingen minipig exposed to gamma radiation in the dose range between 5 and 12
Gy. These results suggest the Gottingen minipig may a suitable model to study GI-ARS. Knowledge of the
natural history as well as a determination of reliable endpoints for the different ARS sequelae, is required
for drug testing. This study is the first step toward determing such requirements and towards evaluating
the feasibility of using the Gottingen minipig for drug efficacy testing to treat the GI-ARS. Additional
studies are necessary to bracket radiation doses causing the GI syndrome in this model and to confirm
validity of endpoints for euthanasia. The views expressed here do not necessarily represent the Armed
Forces Radiobiology Research Institute, the Uniformed Services University of the Health Sciences, or the
Department of Defense.
(PS7-5) Estimating radiation risk by measuring chromosomal rearrangements occurring in pKZ1 mice
1
1
following acute and chronic low-dose radiation exposures. Laura Bannister ; Mandy Serran ; Rebecca
1
1
1
2
Mantha ; Lyndsey Duck ; and Pamela Sykes , Atomic Energy Canada Limited, Chalk River, Canada and
Flinders Medical University, Adelaide, Australia
2
pKZ1 mice contain a transgene allowing quantification of chromosomal DNA inversion events in
vivo arising spontaneously or in response to genotoxic reagents. DNA repair mediated inversion of the
transgene can be considered as a surrogate risk marker for genomic rearrangements associated with
radiation-induced carcinogenesis. The pKZ1 assay is extremely sensitive, with changes in transgene
inversion frequency occurring at doses of ionizing radiation and other mutagens that are orders of
magnitude lower than those eliciting responses in studies using alternate rodent models. The pKZ1 mouse
model is currently being utilized at AECL for two collaborative research projects that examine the effects
of low-LET ionizing radiation, using doses and dose rates that are relevant to environmental, occupational
and medical exposures. One project addresses the true shape of stochastic endpoint dose response curves
at low doses below which the epidemiological risk for cancer induction remains uncertain. Dose response
curves for pKZ1 inversions in spleen and prostate following total body X-ray irradiation do not conform to
Linear-No-Threshold (LNT) expectation of Radiation Protection, indicating that non-targeted effects are
playing an important role at low radiation doses. The aim of this first project is to generate a low-LET
60
splenic pKZ1 dose response curve using Co gamma radiation (mean photon energy 1.25 MeV) for
comparison with previous results obtained with 250kV X-Rays, spanning a dose range 0.01 mGy to 2 Gy
and using doses and dose rates similar to those used in X-Ray irradiation experiments. The second project
compares the biological effects of chronic low-dose tritium exposure for one month or eight months to
equivalent doses of gamma radiation, using doses and dose rates that are relevant to regulatory levels for
tritium in drinking water (10 kBq/L, 1 MBq/L and 20 MBq/L). This project was undertaken to investigate
the health effects of tritium exposures and, in particular, uncertainty concerning the reliability of the
currently used ICRP recommended radiation weighting factor (WR) of 1 for the calculation of committed
354 | P a g e
