Radiation Russian Roulette
The discovery that radiation damages DNA in a new and unexpected way has
raised fears that it may cause a far wider range of diseases than was
Rob Edwards reports
EAT enough arsenic and you'll die. Death is swift and sure. Radiation on
the other hand, is far less predictable. Expose yourself to even a low dose
of radiation and it might or might not kill you some time in the future.
This hit-and-miss effect on the body, along with the fact that it's
invisible, and so mysterious, is why most people have a profound mistrust
Epidemiological studies of survivors from Hiroshima and Nagasaki show that
people started dying of leukemia five years after the bombs were dropped.
It took another 15 years for cancers to develop in the lung, breast and
urinary tract. Scientists have used these and other studies to reduce
emissions from nuclear plants to levels that they predict will keep the
likely number of deaths from radiation-induced disease to a vanishingly
small figure, At present, it's internationally accepted that a member of
the public should not receive more than 1 millisieverts a year. Yet,
despite these safeguards, mistrust of radiation and the nuclear industry
Now, radiation biologists are concluding that the public may well have been
right all along, They have found a previously unknown pathway by which
radiation can subvert living cells, Radiation, they say, may cause a much
wider range at diseases than epidemiological studies predict. Even levels
of exposure below 1 millisievert a year could be harmful, and thousands of
people could face early death as a result, Worst of all, the small doses of
radiation that millions habitually receive could be poisoning the human
gene pool, wreaking damage on future generations. "It is a horrifying
concept, says Eric Wright from the Medical Research Council at Harwell in
Oxfordshire. "But we now have early indications that it may be happening."
Conventional wisdom says that when ionizing radiation hits a living cell,
there are three possible outcomes. Either the cell is unharmed, or it is
killed, or it survives if with its DNA damaged (see Diagram on page 26). If
the cell is not mended by the cell's repair enzymes and the cell divides,
the damage will be passed on to its daughter cells. Depending on the type
of cell and which genes, if any are damaged, the result could be
uncontrolled growth and eventually cancer.
But Wright, who is head of experimental hematology at the MRC's Radiation
and Genome Stability Unit, has found a fourth possibility. "Radiation can
also," he says, "inflict damage on cells that at the moment can only be
detected after they have divided several times." He calls this radiation
induced genomic instability.
The eventual effects of the instability include broken or misshapen
chromosomes and mutated genes, and early cell death. Research from around
the world has shown that it can be produced by neutrons, X-rays, gamma rays
and alpha radiation. In the laboratory, a dozen cell divisions over a
couple of weeks are enough to generate chromosomal defects in up to 30 per
cent of an irradiated cell's progeny. "I regard the phenomenon as
established," says Wright, "There is no doubt that genomic instability is a
real consequence of radiation exposure."
The New Scientist, 1997, October 11th,
Inside the body, this process could have big implications. In an average
lifetime, a human being will experience 1016 cell divisions, mostly in the
first few years of life and during puberty. But stem cells in the bone
marrow, which keep the blood replenished with red and white cells, as well
as cells in the gut and skin, continue to divide throughout adult life.
Likewise, sperm are constantly produced by cell division in adult males, In
these cases, the potential for radiation induced instability to do its
worst appears to be highest.
Wright, Munira Kadhim, and colleagues announced the discovery of genomic
instability in 1992. They exposed stem cells from the bone marrow of mice
to plutonium-238 giving them a dose of about 0.5 grays of alpha radiation,
This is the equivalent of a single alpha particle passing through a cell,
the lowest dose the cell could receive.
The cells were kept in Petri dishes for 11 days until they had divided
between 10 and 13 times, each producing between 10,000 and 100,000 daughter
cells. Wright found the progeny of the irradiated cells contained three and
a half times as many chromosome aberrations as the descendants of cells
that were not irradiated. In a letter to Nature, he concluded that the
"relative biological effectiveness" - a measure of how damaging low-level
radiation can be in the body - for isotopes that emit alpha particles is
In 1994, Wright repeated the experiment with stem cells taken from four
people. After between 10 and 15 divisions, up to 25 percent of the progeny
of cells from two of the individuals were riddled with broken and distorted
chromosomes. The fact that cells from the other two subjects showed no
signs of induced instability may mean that some people carry genes that
protect them from this type of damage, Wright argues.
At least six other laboratories around the world have now found similar
results. Bo Lambert from the Karolinska Institute in Stockholm, for
example, showed that X-rays damage the chromosomes of the descendants of
irradiated human lymphocytes. Robert Ullrich from the University of Texas
in Galveston discovered chromosome aberrations in the offspring of human
breast cells caused by neutron and gamma irradiation. Last year,
researchers from NASA and the University of Naples in Italy reported that
the offspring of skin cells developed chromosome aberrations after exposure
to X-rays and alpha particles. They concluded that genomic instability
could determine late genetic effects and should therefore be carefully
considered in the evaluation of risk for space missions".
These studies all use cells grown in laboratories and so are open to the
criticism that something different might happen in living animals. At least
two experiments however suggest that radiation also causes genomic
instability in vivo. In a previously unnoticed study in 1989, Christian
Streffer from the University of Essen in Germany exposed fertilized eggs of
mice to X-rays. When skin cells were taken from the growing fetuses, they'
contained more chromosome aberrations than cells taken from unirradiated
In addition, last year, Wright and his colleagues at the MRC irradiated
stem cells from the bone marrow of male mice and transplanted them into
female mice. (The transplants and their progeny contained a Y chromosome so
could be easily distinguished from the females' cells.) The researchers
detected "persisting chromosomal instability" in the male cell line up to a
More recently, in order to test his suspicion that some people carry genes
that predispose them to genomic instability, Wright has shown that some
strains of mice are more vulnerable to genomic instability than others. In
one experiment, he exposed bone marrow cells from three strains to
radiation, Daughter cells from two of these strains went on to develop many
chromosome aberrations than tens from the other.
Wright and other radiobiologists are now searching for the mechanisms
behind genomic instability. In one experiment, Wright found abnormal levels
of highly reactive free radicals in cells derived from irradiated cells.
There is good evidence that raised levels of free radicals can induce
chromosomal damage, and Wright believes that a buildup of these chemicals
over several generations could be the root cause of genomic instability.
Keith Baverstock, a senior radiation scientist with the WHO, has a
different theory. He believes radiation could damage a gene for one or two
repair enzymes. DNA is not a static molecule but changes all the time, and
repair enzymes constantly cut out damaged sections and patch them up. If
radiation stops one of these enzymes doing its job, a subsequent error may
not be properly repaired. When the cell divides, its progeny will inherit
this imperfection along with the disabled enzyme, which will carry out
further imperfect repairs, and so on, piling up flaws down the generations.
Finally, the whole thing gets so bad that the whole thing just breaks up
and you get instability," argues Baverstock.
At this point the question becomes the same as that asked for all forms of
DNA damage caused by radiation - how does the damage cause disease? Most
work on this question has focused on cancer and scientists believe that
certain genes may hold the key. If a gene that promotes cell division is
damaged, for example, that cell can divide over and over again. Other
possible contenders are genes such as p53, that normally suppress
development of cancer. If a person's two copies of p53 are damaged, a tumor
is likely to grow.
All these suggestions could be different parts of the same complex puzzle.
Baverstock compares the difficulties of identifying the biological
mechanisms to a long car journey. "You may know that a car started in
Glasgow and finished in Cambridge" he says, "but the number of different
routes it could have taken in between is immense."
Despite the holes in our understanding of induced genomic instability,
Wright feels that we already know enough to start worrying. He believes
that in addition to cancers such as leukemia, it may cause small increases
in a wide range of other diseases. These could include developmental
defects in fetuses, such as deformed limbs and cleft palates and brain
disorders such as Alzheimer's, Parkinson's and motor neuron diseases. But
he stresses that these suspicions are not yet backed up by experimental
The amount of radioactivity needed to induce instability could be tiny.
Wright's director at the MRC Unit, Dudley Good argues that a single alpha
particle is enough to injure a cell and increase the risk of disease. Those
who swallow just one atom of plutonium are hence marginally more likely to
die early. "It's like Russian roulette." says Goodhead.
Wright and Goodhead are not the only ones to be concerned. Two years ago
this month, more than 30 radiobiologists and health specialists from around
the world gathered in Helsinki for a workshop on the public health aspects
of radiation induced genomic instability. They cite 26 studies which, they
say suggest that the accepted rules about how to calculate the biological
impact of radiation should be rewritten, "Genomic instability changes our
way of thinking about how radiation damages cells and produces mutations,"
says Jack Little, professor of radiobiology at the Harvard School of Public
Health in Boston, who attended the workshop.
Last year. participants in the workshop produced a report for the WHO and,
although it was not published, New Scientist has obtained a copy. It
suggests that instability is an early, key event in the process that leads
to cancer. It points out that people with the inherited disorder Fanconi
Anemia develop the same sort of chromosome aberrations seen in radiation
induced instability and about 15 percent of these contract leukemia.
Instability is also a "plausible mechanism" for explaining illnesses other
than cancer, the report says. "It would seem likely that if genomic
instability led to health effects these would not be specific but may
include developmental deficiencies in the fetus, cancer, hereditary
disease, accelerated aging and such non-specific effectsa as loss of immune
competence," Epidemiology would be "powerless" to detect any relationship
between the incidence of such diseases and exposure to radiation, the
report says because the number of people who would suffer from any single
disease would be too low.
Baverstock, who was the main organizer of the Helsinki workshop, and Wright
believe that the world should be more wary of low-level radiation. If
genomic instability is causing unpredicted disease, and if some people are
genetically predisposed to it, the regulatory system starts to look
inadequate. Existing measures meant to protect people - argue Wright and
Baverstock - are less than reassuring.
To check that people do not receive more than 1 millisievert a year, the
British Ministry of Agriculture, Fisheries and Food monitors "critical
groups" of people who, because of their lifestyles, are likely to receive
the highest doses of radioactivity from nuclear plants. The Sellafield
complex in Cumbria has been the largest emitter of radiation in Britain,
discharging radioactive gases into the air and liquid into the Irish Sea.
The critical groups here have included fishermen working in the Irish Sea,
people who eat seaweed and occupants of houseboats moored on contaminated
The underlying assumption is that everybody is equally vulnerable to
radiation, and that possible health effects depend purely on levels of
exposure, but if the critical groups do not contain people who are
genetically predisposed to genomic instability, then this system will
overestimate the level of radiation deemed safe.
These people could then be exposed to levels of radiation that could harm
them. So the number of people to have died or suffer from radiation
released from Sellafield, nuclear weapons tests, the Chernobyl accident,
from medical X-rays and radon in buildings - could be much greater than
anyone has dared to admit.
This is regarded as unscientific scaremongering by Britain's National
Radiological Protection Board at Harwell. Roger Cox, head of the radiation
effects department at the NRPB, does not dispute that his colleagues across
the road at the MRC have found unstable changes in cells descended from
irradiated cells, but he disagrees that they are likely to have any impact
"The basic science is not the problem here, it is their interpretation of
it," Cox argues. "There is no proof that genomic instability leads to
cancer or other diseases, no studies that have shown an association between
illness and instability and there is no hard evidence of any causal
mechanisms. Even if instability causes an increased rate of illness, it
would already be taken into account by existing safety limits. We're quite
some way from having serious doubts about the risk estimates we make," he
In particular, Cox dismisses the suggestion that genomic instability can
cause small increases in a wide range of diseases as "totally speculative".
Although he admits that such an effect cannot be ruled out, he argues that
if it exists, it must be very minor, contained within the statistical noise
of epidemiological studies. "There is rigorous medical surveillance of
Hiroshima and Nagasaki victims," he says. "It would be a surprise if there
was any major effect on any aspect of health that had not been picked up."
Wright concedes that there is no proof that instability causes cancer, but
he argues that it is "highly unlikely" to be irrelevant to the process.
"Cox fails to appreciate," he says, "that the scattergun effect of
instability - small increases in a wide range of diseases would by its very
nature escape the notice of epidemiologists."
Wright also questions the relevance of studies of atom bomb survivors to
the understanding of genomic instability. Extrapolating from a group of
people exposed to a large acute dose of radiation to a group receiving
small, chronic doses may not be valid. Two different mechanisms may be
involved, and it's important to learn if this is the case. "Instead," says
Wright, "the NPRB gets defensive and criticizes everything that does not
fit their corner of the world."
His biggest concern is that instability could blight future generations. He
has collaborated with Brian Lord from the Patterson Institute for Cancer
Research at the Christie Hospital in Manchester in a study that is due to
be published soon. It gives the first clear experimental evidence that
instability can he passed from a male to his offspring in sperm.
Lord found that the pups of male mice exposed to alpha radiation suffered
chromosome aberrations in their bone marrow likely to be associated with
genomic instability. The finding lends support to the controversial theory
advanced in 1990 by the late Martin Gardner from Southampton University
that the children of fathers exposed to radiation at Sellafield run a
higher than normal risk of contracting leukemia.
But Wright and Baverstock fear that the consequences could extend far
beyond the leukemia cases. Millions of people worldwide are exposed to low
level radiation. The damage inflicted on their DNA could be passed to their
children, and to their childrens' children. The human gene pool could be
Furthermore, argue Wright and Baverstock, there is no logical reason why
such damage should be confined to ionizing radiation. Carmel Mothersill
from the Dublin Institute of Technology told meeting in Toulouse and Oxford
last month that the offspring of cells exposed to low levels of cadmium and
nickel also suffer high rates of cell death-a tell-tale sign of genomic
instability. Chemicals in tobacco smoke, air pollution or pesticides might
also destabilize the genome.
These ideas are already irritating scientists working in radiation
protection, who believe that existing safeguards are adequate. Wright and
Baverstock themselves accept that institutional change will be slow and
that there is much still to be learnt about the biology of genomic
instability. In the meantime, they are minimizing their own exposure to
radiation. Baverstock refused dental X-rays that were not medically
necessary. Wright too avoids medical X-rays unless his dentist or doctor
can convince him they are essential. And he does not eat fish from the
Irish Sea for fear of contamination by plutonium from Sellafield.
Further Reading: "Genomic Instability induced by ionizing radiation" by
William Morgan and others, Radiation Research, vol 146, p 247. A full list
of references is on Planet Science.
Source: New Scientist: 11 October 1997
Compliments of Proposition One Committee