12

Understanding health risks from low doses

of ionizing radiation∗

D.G. Thomassen, A. Patrinos

Office of Biological and Environmental Research, SC-72 Office of Science, US Department of Energy,
19901 Germantown Road, Germantown, MD 21701-1290, USA

Epidemiological and toxicological research has long been used to characterize health re-
sponses of populations and individuals to high radiation doses. This information is used to
set exposure standards to protect the public and the workforce. Standards are set using models
that predict unmeasurable cancer frequencies at low radiation doses by extrapolating from the
number of cancers observed following high dose exposures.
Recently, new techniques and instruments have been developed that enable direct mea-
surements of the biological changes induced by low doses of radiation. These research tools
provide new information to help define radiation’s measurable effects on cells and molecules
at environmentally relevant exposures. Such research will underpin the development of future
science-based radiation risk regulatory policy.
Microbeams are being developed that can expose individual cells, or specific parts of cells
such as the nucleus, the cytoplasm, or even specific regions of the nucleus or cytoplasm, to
a wide range of radiation energies (from heavy ions to electrons) and doses (including the
ultimate low dose – a single ion). These instruments will enable critical questions about the
biological effects of very low doses of radiation to be addressed.
Rapid progress in the Human Genome Project has enabled studies on the effects of radia-
tion at the level of the individual gene. The biological effects of high, carcinogenic doses of
radiation can now be compared directly with the effects of low doses for which there is only
sparse and conflicting data as to whether risks for selected cancers increase or decrease.
However, critical questions remain. Are the cellular effects induced by high and low radia-
tion doses identical at the molecular level, differing only quantitatively in proportion to dose?
Do cells recognize changes induced by low doses of radiation the same way they recognize
changes induced by high doses? Do cells, tissues and whole organisms each respond in a
qualitatively similar way to high and low doses of radiation?
* The research summaries described here are not the result of primary scientific research by the authors but were
reported by the principal investigators at a meeting of scientists funded by the DOE Low Dose Radiation Research
Program held March 25–27, 2002. For meeting abstracts, see the program web site at www.lowdose.org.

RADIOACTIVITY IN THE ENVIRONMENT Published by Elsevier Ltd.

VOLUME 7 ISSN 1569-4860/DOI 10.1016/S1569-4860(04)07002-0
 Understanding health risks from low doses of ionizing radiation 13

Observations such as the by-stander effect demonstrate that unirradiated neighbors of cells
exposed to low doses of radiation can exhibit biological responses as if they had been ir-
radiated. The biological mechanisms responsible for this and other phenomena such as the
adaptive response and genomic instability remain to be determined, but they all suggest that
the effects of low doses of radiation cannot be understood by simply extrapolating from the
effects seen at high doses.
Using emerging biological data to help predict health risks from low doses of radiation is
itself a difficult but crucial challenge. For this research to have an impact on radiation risk reg-
ulatory policy, the new data need to be incorporated into biologically plausible mathematical
models that predict risks from low doses of radiation.
The US Department of Energy’s Low Dose Radiation Research Program (www.lowdose.org)
is specifically supporting research to determine health risks from exposures to low levels of
radiation. Together with the results from complementary research programs around the world,
the new scientific information generated in this research program is critical to adequately and
appropriately protect people from radiation and to make the most effective use of national
resources.

1. Introduction

Epidemiological and toxicological research has long been used to characterize health re-
sponses of populations and individuals to high radiation doses. This information is used to
set exposure standards to protect the public and the workforce. Standards are set using models
that predict unmeasurable cancer frequencies at low radiation doses by extrapolating from the
number of cancers observed following high dose exposures.
The US Department of Energy’s Low Dose Radiation Research Program (www.lowdose.org)
was established in 1997, with encouragement from Senator Pete Domenici (Republican Sen-
ator from New Mexico), to improve the scientific basis for the development of risk protection
policies for ionizing radiation that adequately and appropriately protect both workers and the
public while at the same time making the best use of public funds.
A driving reality behind this research program is the fact that we regulate exposure to
low levels of ionizing radiation using the linear no-threshold model, the premise of which is
that there is no safe level of exposure and for which there is also no direct data to prove or
disprove the appropriateness of the model. The difficulty and challenge, from both a policy and
a scientific perspective, was emphasized at a 1999 meeting of international radiation biologists
and policy makers.1 In a consensus statement for the executive summary of the conference
report, the conferees agreed that “the lowest dose at which a statistically significant radiation
risk has been shown is ∼ 100 mSv (∼ 10 rads of X-rays),” yet we regulate radiation exposures
to both workers and the public at much lower levels.
Several key questions need to be answered. Is human health risk from radiation exposure
always proportional to dose? Can any amount of dose increase that risk? Can a single radia-
tion ionization cause cancer? In the past it has been all but impossible to directly measure the
biological effects of radiation doses of less than 10 rads to say nothing of determining their
1 Published in the Executive Summary from Bridging Radiation Policy and Science, an international meeting of
experts held at Airlie House Conference Center, December 1–5, 1999.
14 D.G. Thomassen, A. Patrinos

potential health effects. Today, we have new techniques and instruments that enable direct
measurements of the biological changes induced by low doses of radiation. Advances in in-
strumentation and in research, especially in genomics, provide new information to help define
radiation’s measurable effects on cells and molecules at environmentally relevant exposures.
Such research will, hopefully, underpin the development of future science-based radiation risk
regulatory policy.
Traditionally, the biological effects of radiation exposures have been viewed as one-hit phe-
nomena, that is, only the hit cell was affected. Now, it is widely accepted that the interaction
of ionizing radiation with living systems is far more complex involving higher order biologi-
cal effects such as communication between irradiated and unirradiated cells and tissue effects.
For this reason, a significant challenge for scientists today is to conduct research on the bio-
logical effects of radiation at all levels of biological organization – from molecules to cells to
tissues to organisms.
The DOE Low Dose Radiation Research Program focuses its efforts in four general areas:
• Low dose radiation versus normal metabolic oxidation – are the damage and biological
responses the same or different?
• Are there thresholds for the biological effects of low doses of radiation?
• Are there genetic factors that affect an individual’s risk from or sensitivity to low doses of
ionizing radiation?
• How should we communicate the research results?

2. Low dose radiation versus normal metabolic oxidation

An interesting quandary is whether low doses of ionizing radiation simply increase, in a

strictly quantitative manner, the amount of damage induced in cells as a result of normal
oxidative processes and the biochemistry of life. If this is the case, it could be proposed that
normal cellular mechanisms that recognize and efficiently repair this type of damage might
be able to do the same for the additional damage induced by low doses of ionizing radi-
ation thereby making some yet- to-be-defined low levels of ionizing radiation no greater a
biological risk than normal cellular processes. Alternatively, low doses of ionizing radiation
may induce damage that is qualitatively different from that normally found in cells and some
of this damage might not be as efficiently recognized or repaired. If this later possibility is
shown to be the case, each increment of low dose ionizing radiation might increase the risk of
radiation-induced biological effects.
Research reported at the Low Dose Radiation Research Program grantee and contractor
workshop (Betsy Sutherland, Principal Investigator) suggests that low doses of ionizing radi-
ation may not simply increase the types of damage induced by normal metabolic processes.
Cells irradiated with as little as 3 rads of radiation showed clustered DNA lesions not seen in
unirradiated controls. This difference may either reflect a threshold of normal damage recog-
nition and repair processes or may be evidence for qualitative differences in the types of
damage induced by low doses of ionizing radiation compared to the damage induced by nor-
mal cellular processes. Either way, these results represent the types of studies that are needed
if we are to actually study the biological effects of low doses of ionizing radiation. Further,
the relevance of this observation for human health risk also needs to be determined.
 Understanding health risks from low doses of ionizing radiation 15

3. Biological responses to low doses of radiation

New technologies and instruments are also playing an important role in studies of the biolog-
ical effects of ionizing radiation. Microbeam irradiators are important tools being developed
and used in a number of laboratories around the world. These instruments can be used to
expose individual cells, or specific parts of cells such as the nucleus, the cytoplasm, or even
specific regions of the nucleus or cytoplasm, to a wide range of radiation energies (from heavy
ions to electrons) and doses (including the ultimate low dose – a single ion). These instruments
are enabling critical questions about the biological effects of very low doses of radiation to
be addressed. For example, microbeam irradiators can be used to help identify and define the
target size for radiation – the nucleus? the cytoplasm? They can help scientists determine the
role of cell-to-cell communication between irradiated and unirradiated cells, information that
is needed help define the effective biological target and target size for radiation. They can
also help define the effects of normal tissues surrounding an individual or small number of
irradiated cells on the ultimate biological response.
In recent years, a number of biological responses to radiation have challenged the traditional
view of radiation effects. For example, observations such as the by-stander effect, made in a
number of cell culture systems, demonstrate that unirradiated neighbors of cells exposed to
low doses of radiation can exhibit biological responses as if they had been irradiated. Now,
there is evidence that by stander effects can also be observed in intact tissues (Kevin Prise,
Principal Investigator). The biological mechanisms responsible for this phenomenon, whether
in vitro or in vivo, remains to be determined, but the observations suggest that the effects of
low doses of radiation cannot be understood by simply extrapolating from the effects seen at
high doses. Interestingly, a number of studies reported in the literature over many years on
clastogenic factors in people or animals exposed to radiation may also represent examples of
bystander-related phenomena in vivo. A key impact of the bystander phenomenon is that it
alters the “traditional” target size for radiation-induced damage, changing our view, not only
of how individual cells respond to radiation but, possibly, how tissues respond as well.
A fascinating merger of traditional radiation biology with a set of tools emerging from
current capabilities in DNA sequencing and genomics is the analysis of the individual genes
that are expressed in response to radiation exposures. While it is not surprising that radiation
exposures induce the expression of unique sets of genes, what is surprising are the responses
induced by high (200 rads) and low (10 rads) doses of radiation. While common sets of genes
are induced in different cell and tissue systems in response to high and low doses of radiation,
there are an equal, if not greater, number of genes whose expression is uniquely induced by
high and low doses of radiation. In other words, low doses of radiation induce the expres-
sion of a substantial number of genes not induced by high doses of radiation and vice versa
(Andy Wyrobeck, Al Fornace, David Chen, Principal Investigators). Clearly, with respect to
the induction of gene expression, high doses of radiation are not simply more of a low dose
of radiation – an observation with potentially dramatic implications for the extrapolation of
high dose effects to low doses of radiation, though the relationship between this observation
and biological risk clearly needs to be determined.
New genetic probes have also been used to better characterize the detailed nature of
radiation-induced chromosomal aberrations, a traditional indicator of radiation damage. Ad-
vanced chromosome “painting” techniques now demonstrate that radiation causes highly com-
16 D.G. Thomassen, A. Patrinos

plex chromosomal aberrations that can not be accounted for by “simple hit theory” (Bill Mor-
gan, Principal Investigator).
Other recent results also suggest differences in the biological responses at high and low
doses of radiation. Low doses of radiation (< 3 rads) have been shown, under certain con-
ditions, to reduce the frequency cell transformation below the frequency in unirradiated con-
trols (Les Redpath, Principal Investigator). Low doses of radiation (0.5–4 rads) have also been
shown to be better at killing cells than high doses (Peter Johnson, Principal Investigator). As
with the other phenomena described here, the relationship between this observation and bio-
logical risk needs to be determined; however, these observations also demonstrate that there
is not a clear linear relationship between the biological effects of radiation at high and low
doses.
Research is also underway in a number of areas for which it is still too early to tell what
the outcomes will be with respect to the effects of radiation in the 1 to 10 rad, or below,
region. Radiation has been shown to induce genomic instability in both isolated cells and
intact animals, a process in which radiation exposure results in the generation of chromoso-
mal instability (seen as chromosomal aberrations) many generations after the initial exposure.
Genomic instability is also a feature of many cancers. If it is possible to establish a clear rela-
tionship between exposures to low doses of radiation and the induction of genomic instability,
it will be an important link between a traditional high radiation dose endpoint, a cancer-related
phenotype, and low doses of radiation.

4. Genetic susceptibility to low doses of radiation

Rapid progress in the human genome project has also made it more likely that we will be
able to determine if there are specific genes/phenotypes that make some individuals more
susceptible, or even more resistant, to the adverse effects of low doses of radiation. A num-
ber of radiation sensitive phenotypes, e.g., Fanconi’s anemia and xeroderma pigmentosum,
have previously been described based on the dramatic phenotypes of individuals homozygous
for specific genes. Cohorts of individuals who received high doses of radiation for medical
treatment are now being reexamined for variable radiation sensitivity and, eventually, using
human DNA sequence data to see if there are additional genes that make individuals more or
less sensitive to radiation.
While important information scientifically, the long-term results of these studies also have
important and difficult ethical and societal implications. Should individuals who are geneti-
cally at greater risk for adverse effects of radiation be prevented from having certain types
of jobs? Should employers even have access to this information if it is available or obtain-
able? Would all individuals chose to know this information even about themselves? These are
difficult questions with equally difficult and uncertain answers.
Using emerging biological data to help predict health risks from low doses of radiation is
itself a difficult but crucial challenge. For this research to have an impact on radiation risk
regulatory policy, the new data needs to be incorporated into biologically plausible mathe-
matical models that predict risks from low doses of radiation. Developing such models is a
complex task in itself. The path to the generation of such models is far from certain. Current
“biologically based” risk models are “informed” by biology but generally only use the most
 Understanding health risks from low doses of ionizing radiation 17

rudimentary biological information such as cell proliferation, differentiation, and the general
concepts about the role of mutations and variable numbers of biological “steps” that are in-
volved in the development of cancer. The different types of biological information described
here will not be equally useful, if useful at all, in the development of an entirely new gen-
eration of biologically based risk models. However, it is clear that new models are needed
to serve as a key interface or interpreter between the detailed biological effects of radiation
and the development of science-based risk policies that adequately and appropriately protect
people from the adverse effects of radiation.

5. Communicating risks of low dose radiation

As if the science of low dose radiation biology was not a great enough challenge, an even
greater challenge is the open and clear communication of this new science and its biological
and health risk implications to the public. For many reasons, both good and bad, reasonable
and unreasonable, the public generally has a fear and distrust of radiation that far exceeds
what current scientific wisdom tells us is reasonable. Many studies of risk perception have
shown that people generally rank familiar risks from things over which they have a choice,
such as driving a car or even high dose medical therapy, as less of a threat than things like
radiation from medical waste or from living next to a nuclear power plant, over which they
have little or no choice and for which they generally have no real-life experiences on which
to base their perception.
While the public generally has a more positive than negative view of science, the public
perceptions or understanding of the risks of low doses of radiation, be they greater or lesser
than currently predicted by the linear no-threshold models, will not likely be changed in the
near future simply from the results of new scientific research. Changing the perceptions of
the public about radiation from a more emotion-based reaction to a more science-based un-
derstanding will take many years, likely decades, of rebuilding trust between the public and
radiation scientists, radiation policy makers, and public and private organizations with respon-
sibility for radiation – from medical uses to energy production to waste disposal.
The US Department of Energy’s Low Dose Radiation Research Program is specifically
supporting research, such as that described here, to determine health risks from exposures
to low levels of radiation. Together with the results from complementary research programs
around the world, the new scientific information generated in this research program is critical
to adequately and appropriately protect people from radiation and to make the most effective
use of national resources.