Page 85 - 2014 Printable Abstract Book
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threshold effects poses major challenges when attempting to integrate radiobiology and epidemiology.
Might these challenges be overcome given a proper framework/s Epidemiology – few epidemiologic
investigations of exposed populations have attempted to integrate biology with epidemiology. One
example is the WECARE study where radiation-induced breast cancer is being evaluated in the presence
of inherited genetic mutations in genes that predispose to breast cancer, such as ATM, BRAC1, BRAC2 and
CHEK2. Does radiation interact with a genetic susceptibility to greatly enhance future cancer risk? Clinical
relevance – medicine is focused on preventing and curing illness. Radiation is a cure and a cause of cancer.
Does an integration of biology and epidemiology to further understand low-dose radiation effects have
added clinical value? Might the uses of radiation be modified if individual inherited genetic mutations in
cancer genes, GWAS risk alleles or Genetic Risk Scores were found to be predictive of cancer in the
presence of radiation? Closing the Gap – what framework/s might be considered to effectively integrate
biology with epidemiology to enhance the understanding of low dose radiation effects and to reduce the
uncertainties in estimating effects below 100-200 mSv? For example, could “the key-event” approach be
used in conjunction with high-quality radiation epidemiology data to reduce overall uncertainty in low
dose/low-dose rate cancer and noncancer risk estimates?
(S2301) Molecular, cellular and tissue responses to ionizing radiation. Jac A. Nickoloff, PhD
Colorado State University Department of Environmental and Radiological Health Sciences, Ft. Collins, CO
It has proven difficult to evaluate risks of cancer and other diseases to low dose, and low dose
rate exposures of human populations to ionizing radiation from background sources, diagnostic medical
procedures, work environments, and radiological accidents/incidents. The application of advanced
molecular and cell biological tools provides insight into subtle cell responses to a wide range of doses,
such as the graded activation of DNA damage response signaling pathways and changes in gene expression
profiles. DNA damage response pathways, including DNA damage checkpoints and DNA repair, play critical
roles in cancer suppression in the presence and absence of exogenous genotoxic exposure, because these
pathways suppress genome instability that drives cancer. DNA damage can be detected at very low doses
by analyzing chromatin modifications and protein recruitment to DNA lesions, observed as subnuclear
foci. Checkpoint activation can be observed by analyzing cell cycle arrest, or post-translational
modification of checkpoint proteins. Checkpoints are not “on or off” but show graded responses, and
genetically regulated, cell cycle-specific threshold effects. DNA repair efficiency varies with the level of
damage, with more efficient repair at lower doses. Low doses can induce delayed genome instability that
can persist for weeks after an exposure. Low doses can also induce adaptive responses that promote
survival or suppress genome instability when cells are exposed to a subsequent higher dose, potentially
reflecting low-dose activation of DNA damage response pathways. Bystander effects are seen in
unexposed cells in proximity to exposed cells; such effects can occur over great distances in organisms,
e.g., abscopal effects. Radiation induces epigenetic changes in DNA and chromatin that alters gene
expression, and there have been efforts to link these changes to relevant endpoints such as genome
instability and tumorigenesis. Although some biological effects of radiation show linear dose responses
(e.g., DNA damage), others are non-linear (e.g., delayed genome instability), reflecting the complex
interplay of DNA repair, intra- and extracellular signaling pathways, and threshold effects. This complexity
poses major challenges when attempting to integrate radiobiology and epidemiology.
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Might these challenges be overcome given a proper framework/s Epidemiology – few epidemiologic
investigations of exposed populations have attempted to integrate biology with epidemiology. One
example is the WECARE study where radiation-induced breast cancer is being evaluated in the presence
of inherited genetic mutations in genes that predispose to breast cancer, such as ATM, BRAC1, BRAC2 and
CHEK2. Does radiation interact with a genetic susceptibility to greatly enhance future cancer risk? Clinical
relevance – medicine is focused on preventing and curing illness. Radiation is a cure and a cause of cancer.
Does an integration of biology and epidemiology to further understand low-dose radiation effects have
added clinical value? Might the uses of radiation be modified if individual inherited genetic mutations in
cancer genes, GWAS risk alleles or Genetic Risk Scores were found to be predictive of cancer in the
presence of radiation? Closing the Gap – what framework/s might be considered to effectively integrate
biology with epidemiology to enhance the understanding of low dose radiation effects and to reduce the
uncertainties in estimating effects below 100-200 mSv? For example, could “the key-event” approach be
used in conjunction with high-quality radiation epidemiology data to reduce overall uncertainty in low
dose/low-dose rate cancer and noncancer risk estimates?
(S2301) Molecular, cellular and tissue responses to ionizing radiation. Jac A. Nickoloff, PhD
Colorado State University Department of Environmental and Radiological Health Sciences, Ft. Collins, CO
It has proven difficult to evaluate risks of cancer and other diseases to low dose, and low dose
rate exposures of human populations to ionizing radiation from background sources, diagnostic medical
procedures, work environments, and radiological accidents/incidents. The application of advanced
molecular and cell biological tools provides insight into subtle cell responses to a wide range of doses,
such as the graded activation of DNA damage response signaling pathways and changes in gene expression
profiles. DNA damage response pathways, including DNA damage checkpoints and DNA repair, play critical
roles in cancer suppression in the presence and absence of exogenous genotoxic exposure, because these
pathways suppress genome instability that drives cancer. DNA damage can be detected at very low doses
by analyzing chromatin modifications and protein recruitment to DNA lesions, observed as subnuclear
foci. Checkpoint activation can be observed by analyzing cell cycle arrest, or post-translational
modification of checkpoint proteins. Checkpoints are not “on or off” but show graded responses, and
genetically regulated, cell cycle-specific threshold effects. DNA repair efficiency varies with the level of
damage, with more efficient repair at lower doses. Low doses can induce delayed genome instability that
can persist for weeks after an exposure. Low doses can also induce adaptive responses that promote
survival or suppress genome instability when cells are exposed to a subsequent higher dose, potentially
reflecting low-dose activation of DNA damage response pathways. Bystander effects are seen in
unexposed cells in proximity to exposed cells; such effects can occur over great distances in organisms,
e.g., abscopal effects. Radiation induces epigenetic changes in DNA and chromatin that alters gene
expression, and there have been efforts to link these changes to relevant endpoints such as genome
instability and tumorigenesis. Although some biological effects of radiation show linear dose responses
(e.g., DNA damage), others are non-linear (e.g., delayed genome instability), reflecting the complex
interplay of DNA repair, intra- and extracellular signaling pathways, and threshold effects. This complexity
poses major challenges when attempting to integrate radiobiology and epidemiology.
83 | P a g e
