Page 167 - 2014 Printable Abstract Book
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care. A shift in the lethality was also observed between LINAC and Co sources. Neutrophils, lymphocytes
and platelets decline predictably and recover in a dose-related manner with platelet recovery incomplete
even at 45 days. The hematopoietic and cytokine changes are consistent among the institutions and with
other well characterized models. CONCLUSIONS: The MP appears to be a reasonable large animal model
test species for h-ARS. The results from the lethality, natural history and biomarker studies under
harmonized parameters yield a model with sufficient reproducibility for examining the efficacy of MCMs.
The views expressed here do not necessarily represent the Armed Forces Radiobiology Research Institute,
the Uniformed Services University of the Health Sciences, the Department of Defense, or the Department
of Health and Human Services. Funded by BARDA Inter-Agency Agreement No.750113PR970019 and
BARDA Contracts HHSO100201100004I, and HHSO1002011000010I, Department of Health and Human
Services.
(PS2-55) Development of a pediatric mouse model of the hematopoietic syndrome of the acute
radiation syndrome (H-ARS) - radiation dose/lethality response relationship (DRR). Rajendran
1
1
1
1
1
Sellamuthu, PhD ; Artur Plett, PhD ; Alexa Fett, BS ; Sasidhar Vemula, PhD ; Carol H. Samson, M.S. ; Hailin
1
3
2
1
1
Feng, M.S. ; Hui Lin Chua, PhD ; Nathan Garrison, A.S. ; Thomas J. MacVittie, PhD ; Gregory Tudor, BS ;
3
1
and Catherine Catherine, PhD, Indiana University School of Medicine, Indianapolis, IN ; University of
3
Maryland School of Medicine, Baltimore, MD ; and Epistem Ltd, Manchester, United Kingdom
2
Development of effective medical countermeasures (MCM) to treat Acute Radiation Syndrome
(ARS) in pediatric and elderly populations is hampered by the lack of suitable animal models representing
such groups. According to the FDA’s Animal Rule, “any MCM developed for ARS would need to be shown
to be safe and effective in special populations”, which are likely more radiosensitive than adults. We have
previously reported baseline body weights, CBC, and preliminary radiosensitivities in C57BL/6 mice aged
3 through 8 weeks as a first step in developing a pediatric hematopoietic ARS (H-ARS) model (Sellamuthu
et al, RRS 2013, meeting abstract). The current study further characterizes this model by examining
gastrointestinal parameters and the radiation dose/lethality relationship of each age group of mice. The
small and large intestinal diameter increased with age, which was most pronounced between 3-4 weeks
of age (time of weaning) in the small intestine and 3-5 weeks in the large intestine. The number of crypts
per circumference increased in line with increasing circumference, although the number per mm
remained similar, until approximately 7 weeks when numbers reduced slightly. Crypt widths were similar
for most ages, except in the 3 w/o mice where they were slightly smaller in the upper ileum. To establish
the DRR for estimation of LDXX/30 values, groups of 23-31 mice aged 3 through 8 weeks were exposed to
radiation doses ranging from 600 to 875cGy, provided autoclaved acid water and wet feed, and monitored
for moribundity and morbidity for 30 days. Preliminary results suggest that 3 w/o weanlings are more
radiosensitive than all other pediatric age groups with an LD50/30 of approximately 700-750cGy, whereas
the LD50/30 of mice aged 4 to 8 weeks appears to be ~50-60cGy higher. Similar to adult C57BL/6 mice,
females survived better than males except 3 and 4 w/o, where males survived better. These data are a
first step in developing a pediatric H-ARS model for use in efficacy testing of MCM against radiation in
accordance with the FDA's Animal Rule for the pediatric population. Further development of this pediatric
murine model of H-ARS will determine the efficacy of known MCM and correlation with primitive
hematopoietic parameters in each age group of mice. Funded by NIAID Contract HHSN272201000046C.
165 | P a g e
care. A shift in the lethality was also observed between LINAC and Co sources. Neutrophils, lymphocytes
and platelets decline predictably and recover in a dose-related manner with platelet recovery incomplete
even at 45 days. The hematopoietic and cytokine changes are consistent among the institutions and with
other well characterized models. CONCLUSIONS: The MP appears to be a reasonable large animal model
test species for h-ARS. The results from the lethality, natural history and biomarker studies under
harmonized parameters yield a model with sufficient reproducibility for examining the efficacy of MCMs.
The views expressed here do not necessarily represent the Armed Forces Radiobiology Research Institute,
the Uniformed Services University of the Health Sciences, the Department of Defense, or the Department
of Health and Human Services. Funded by BARDA Inter-Agency Agreement No.750113PR970019 and
BARDA Contracts HHSO100201100004I, and HHSO1002011000010I, Department of Health and Human
Services.
(PS2-55) Development of a pediatric mouse model of the hematopoietic syndrome of the acute
radiation syndrome (H-ARS) - radiation dose/lethality response relationship (DRR). Rajendran
1
1
1
1
1
Sellamuthu, PhD ; Artur Plett, PhD ; Alexa Fett, BS ; Sasidhar Vemula, PhD ; Carol H. Samson, M.S. ; Hailin
1
3
2
1
1
Feng, M.S. ; Hui Lin Chua, PhD ; Nathan Garrison, A.S. ; Thomas J. MacVittie, PhD ; Gregory Tudor, BS ;
3
1
and Catherine Catherine, PhD, Indiana University School of Medicine, Indianapolis, IN ; University of
3
Maryland School of Medicine, Baltimore, MD ; and Epistem Ltd, Manchester, United Kingdom
2
Development of effective medical countermeasures (MCM) to treat Acute Radiation Syndrome
(ARS) in pediatric and elderly populations is hampered by the lack of suitable animal models representing
such groups. According to the FDA’s Animal Rule, “any MCM developed for ARS would need to be shown
to be safe and effective in special populations”, which are likely more radiosensitive than adults. We have
previously reported baseline body weights, CBC, and preliminary radiosensitivities in C57BL/6 mice aged
3 through 8 weeks as a first step in developing a pediatric hematopoietic ARS (H-ARS) model (Sellamuthu
et al, RRS 2013, meeting abstract). The current study further characterizes this model by examining
gastrointestinal parameters and the radiation dose/lethality relationship of each age group of mice. The
small and large intestinal diameter increased with age, which was most pronounced between 3-4 weeks
of age (time of weaning) in the small intestine and 3-5 weeks in the large intestine. The number of crypts
per circumference increased in line with increasing circumference, although the number per mm
remained similar, until approximately 7 weeks when numbers reduced slightly. Crypt widths were similar
for most ages, except in the 3 w/o mice where they were slightly smaller in the upper ileum. To establish
the DRR for estimation of LDXX/30 values, groups of 23-31 mice aged 3 through 8 weeks were exposed to
radiation doses ranging from 600 to 875cGy, provided autoclaved acid water and wet feed, and monitored
for moribundity and morbidity for 30 days. Preliminary results suggest that 3 w/o weanlings are more
radiosensitive than all other pediatric age groups with an LD50/30 of approximately 700-750cGy, whereas
the LD50/30 of mice aged 4 to 8 weeks appears to be ~50-60cGy higher. Similar to adult C57BL/6 mice,
females survived better than males except 3 and 4 w/o, where males survived better. These data are a
first step in developing a pediatric H-ARS model for use in efficacy testing of MCM against radiation in
accordance with the FDA's Animal Rule for the pediatric population. Further development of this pediatric
murine model of H-ARS will determine the efficacy of known MCM and correlation with primitive
hematopoietic parameters in each age group of mice. Funded by NIAID Contract HHSN272201000046C.
165 | P a g e
