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expert reaction to study looking at low doses of radiation in medical imaging and mutations in cell cultures

Research, published in PLOS Genetics, reports that low doses of radiation used in medical imaging may lead to mutations in cell cultures.

 

Prof Geraldine Thomas, Professor of Molecular Pathology, Imperial College London, said:

“This is an interesting paper that seeks to investigate the how various types of DNA repair affect random integration of DNA from non-chromosomal sources following a double strand break. 

“This paper should not be taken as evidence that low dose radiation exposure is likely to result in DNA integration when used in diagnostic procedures in vivo, nor should this work be taken for evidence that exposure to low dose radiation results in cancer in man. 

“In terms of the mechanisms by which this might occur it is interesting, but caution should be taken before extrapolating results on cell lines (murine or human) into the likely effects of radiation in vivo in man.  Cell lines are produced as a result of clonal selection in vitro – this process results in a change in the genetic make up of the cell line relative to the original cell, frequently making the cell lines more genetically unstable, which presumably must come about from a certain amount of derangement in the cell’s original DNA repair mechanisms.  This might make cell lines more likely to tolerate insertion of DNA from non-chromosomal sources compared with cells in vivo.  The authors themselves urge caution in the interpretation of their data.  It is possible that the mechanisms that they have identified in this study would not occur in in vivo in the mouse, never mind in man, and further experiments would therefore need to be carried out. 

“Extensive genomics studies in human cancers show that there are multiple changes in the DNA of cancer cells.  There is considerable evidence from studies in humans that low dose radiation results in extremely small increases in the probability of cancer arising many years later whereas exposure to the effects of lifestyle factors such as alcohol, smoking and even obesity result in much higher risks1.  It should also be remembered that diagnostic radiation procedures are only carried out when there is a clinical need.  The benefit of carrying out an investigation using radiation at low doses may considerably outweigh any infinitely small increase in the risk of possible cancer many years later.”

1. see https://www.oxfordmartin.ox.ac.uk/downloads/restatements/Oxford%20_Martin%20_Restatement5_Radiation.pdf for a review of the evidence in this area.     

 

Prof Derek Hill, Professor of Medical Imaging Science, UCL, said:

“It has been known for more than a century that exposure to radiation such as x-rays can damage cells.  These high doses can cause predictable damage, eg: causing blindness as a result of cataract formation, or they can increase the risk of cancer. The question this research addresses is, how harmful are low doses of radiation, such as from modern x-ray CT scanners, to human cells. Perhaps surprisingly, this is an area of considerable debate in the research community. 

“A lot of the data on serious illness from radiation comes from people who were exposed to very high doses of radiation eg: people working with radiation before its risks were known, those exposed to high doses from atomic bombs, and those involved in accidental release of radiation eg: Chernobyl.  A lot of the basic science on radiation biology has been done on high dose radiation used in treating cancer.  And studying low doses is complicated by the fact that people are exposed to lots of natural background radiation at low doses all the times – such as from the rocks and from cosmic rays (especially during plane travel).

“Given most of the historical data about radiation causing cancer is from people exposed to high doses, scientists have to extrapolate this data to estimate the risk from lower dose. Scientists have debated over recent years whether the risk of cancer from x-rays has a “straight line” relationship with dose, or whether the line is curved. And if the relationship is a curved line, is the risk of low dose higher or lower than would be predicted from a straight line?  Historically, it has normally been thought that the straight line extrapolation is a prudent approach.

“The research in this paper addresses this question with some basic science on cell cultures. It finds a surprisingly high amount of damage caused by low energy x-rays compared to what has previously been expected.    This might suggest that the straight line extrapolation of cancer effects underestimates the true cancer risk.

“However, as the authors themselves state, the experiments described are basic biology: they don’t directly answer the question as to whether these low doses cause more cancer than previously thought. But the data does suggest further research into the health implications of low dose x-ray exposure is needed.  This is particularly topical as it is becoming more common to give children x-ray CT scans to help diagnose and plan their treatments, and the risk of cancer is especially important to understand in children who have the longest time for these cancers to subsequently develop. “

 

Prof Jim Smith, Professor of Environmental Science, University of Portsmouth, said:

“This is an interesting study of the DNA damage effects of radiation on mammalian cell cultures. It adds to our knowledge on genetic damage by ionising radiation and opens up interesting avenues for more research.

“But the authors are wrong to imply that low dose radiation was previously believed not to damage DNA. Current biological understanding, as well as radiation protection guidance and legislation, assumes that even very low dose radiation can potentially cause genetic mutation. Extensive epidemiological evidence shows that the low radiation doses in medical diagnostic procedures present a tiny health risk. As current guidance says, doctors and radiographers should consider this low risk against the medical benefit of the particular diagnostic procedure before exposing patients. I don’t think that the findings of this study should be of concern to patients undergoing diagnostic X-Ray and CT scans.

“I agree with the authors that translating radiation’s effects on lab-grown cell cultures to effects in the body is premature.”

 

Prof Malcolm Sperrin, Director of the Department of Medical Physics and Clinical Engineering, Oxford University Hospitals NHS Trust, said:

“The exposure of any replicating cells to ionising radiation is known to present a risk and this has been accepted wisdom for many decades.  The model usually used is the Linear No-Threshold Model (LNTM) which enables us to calculate a risk based upon even the smallest exposures.  The incidence of radiation induced harm such as DNA damage is of the greatest concern, but it remains a fact that the actual side effects of radiation to patients who are undergoing treatment or imaging is well managed in the context of managing whatever condition they present with.  Some researchers make a case for radiation exposure at the lowest levels to be considered as safe.  The study is highly valuable in that it may provide further insight into the dynamics of DNA damage since as correctly pointed out in the article, the study is not human equivalent and the complex factors of tissue repair, spontaneous cell death, possible hormesis and apoptosis may differ from a living species and may be controllable aspects of further study.”

 

Mr Jim Thurston, Medical Radiation Protection Expert, Institute of Physics and Engineering in Medicine, said:

Does the press release accurately reflect the science? 

“Yes, it does.

Is this good quality research?  Are the conclusions backed up by solid data? 

“Yes, it would appear so, although I am not a cell biologist.  However, there could perhaps be more information given in the paper about the conditions used for the irradiation of the cells for me to comment on the radiation physics aspects.  What is clear is that higher energy gamma rays from the Caesium-137 source, and lower energy x-rays from a CT Scanner were used to irradiate the cells.  This research has not as yet considered irradiating the cells to other ionising radiations – such as to alpha or beta particles from radioactive substances.

How does this work fit with the existing evidence? What have other studies found about the radiation used in common medical imaging procedures? 

“It adds to an existing and increasing number of published papers that show a range of responses of cells irradiated at low doses in-vitro – some of those previous papers show an unexpectedly increased sensitivity in cells in agreement with this paper – other show the opposite, highlighting the large uncertainties in the data at these low doses and further work required on this subject.

Have the authors accounted for confounders?  Are there important limitations to be aware of? What needs to happen next?

“The authors, and press release, have pointed out that this is an in-vitro study and that much more work would be required to translate the results to predictions of what would happen in-vivo – i.e. in a human being exposed to radiation.  However, they have not tried to identify the confounders that might explain their results.

What are the implications in the real world?  Is there any overspeculation? 

“As above, the authors and press release are sensibly cautious in stating the implications of the research.

What is the current guidance around common medical imaging and radiation?

“The international and national framework of radiation protection legislation and guidance is currently based on a simple model that suggests that doubling the radiation dose leads to a doubling of the risk of cell mutations leading to cancer.  It is based on assumptions from evidence of exposures at much higher doses (including those received at Hiroshima and Nagasaki) but is considered a sensible for establishing a framework of requirements for employers to protect their staff, visitors (including patients) and the public from their work with ionising radiation.  For patients exposed to ionising radiation by having medical imaging procedures, it is a requirement of the law for a specialist practitioner such as a Consultant Radiologist to justify the exposure – i.e. to decide that the benefit of diagnosing the patient (and then choosing the right treatment) outweighs all the risks from the procedure including from the radiation exposure.  It is a further requirement that the amount of radiation used for the medical imaging procedure is optimised – i.e. it is the lowest possible, whilst still getting images of sufficient quality that give the doctor enough information to make a diagnosis.

Is it surprising that ‘low doses of radiation, in the upper range of common diagnostic procedures, create mutations through inserted DNA even more efficiently than the much larger doses studied previously.’ Why could this be happening?

“This study, as with others, suggests that at low doses this relationship between dose and risk is more uncertain than our current simple model would imply.  However, it must also be pointed out that at such low doses the absolute risks to people from the radiation are very low in comparison to the overall lifetime cancer incidence rates, and from environmental and other cancer risks (such as smoking, pollution, etc.)

 

Dr Stewart Redman, Radiation Safety Adviser at The Royal College of Radiologists, said:

“There is already established evidence that shows ionizing radiation – at the level used in hospital scanning – can cause an increased risk of DNA damage.

“This appears to be a good robust study, but also comes with the caveat that more research needs to be done to determine real-world impact, especially because variables like patient biology and age, and the frequency and location of radiation exposure, need to be accounted for.     

“Because exposure to ionizing radiation has been linked to cell damage, both medical imaging and cancer treatments that use X-rays are tightly regulated and monitored in hospitals.

“Doctors have a legal and clinical responsibility to ensure that only the most appropriate X-ray related test or treatment are requested and used. The risk and benefit of procedures are carefully weighed and balanced in the interest of patient diagnosis and care, and clinicians ensure any radiation dose used is kept as low as possible.” 

 

Mr David Dommett, Chair, The Society for Radiological Protection’s Medical Committee, said:

“These are interesting findings from an investigation of how ionising radiation, of the kind used in medical diagnostic procedures, affects DNA in cell cultures in the laboratory. The paper reports surprising results on the mechanisms of the interaction of radiation with cells. As the authors say, the results must be confirmed by other experiments, including those using laboratory animals.  A greater understanding of mechanisms of radiation biology is important to advance knowledge of radiation effects. However, the current system of radiological protection assumes that even small doses of radiation, such as those received from natural background radiation or from medical imaging, carry some risk, although very small, and the paper does not alter this position.  The principles of justification and optimisation are followed so that the risk of any radiation dose is always considered alongside the benefit to the patient as part of the decision process on whether to carry out a medical imaging procedure and what the most appropriate procedure should be.”

 

Low dose ionizing radiation strongly stimulates insertional mutagenesis in a γH2AX dependent manner’ by Zelensky et al. is published in PLOS Genetics.

DOI: 10.1371/journal.pgen.1008550

 

Declared interests:

Prof Geraldine Thomas: “No conflicts of interest.”

Prof Derek Hill: “No conflicts of interest.”

Mr Jim Thurston: “No conflicts of interest.”

None others received.

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