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Biological effects of low-dose radiation: of harm and hormesis

Tommaso Gori, Thomas Münzel
DOI: http://dx.doi.org/10.1093/eurheartj/ehr288 First published online: 23 August 2011

This editorial refers to ‘Cellular adaptive response to chronic radiation exposure in interventional cardiologists’, by G.L. Russo et al., doi:10.1093/eurheartj/ehr263

Economic growth, technological advancements, an increased tendency to rely on instrumental findings, and–not least—the phenomenon called defensive medicine have led in the past decades to an exponential growth in the use of medical imaging techniques.

A wider use of potentially dangerous technologies should, however, come with a more thorough awareness of their implications. Knowledge of the risks, costs, and benefit of the use of each medical intervention is obligatory in our profession. However, studies show that we largely underestimate (or are unaware of) the implications of the examinations we prescribe.1

It is therefore our responsibility to be aware of, and most importantly to try and limit, the possible negative medical implications of this trend.

Toxicity and compensatory mechanisms

Although operators are not (or at least should not be) exposed to the X-ray beam, they receive scatter radiation reflected from the patient or from the laboratory walls to an extent that (like the complexity of the procedures they perform) is extremely variable, and may be comprised between 0.04 and 38 µSv per study.2,3

These doses of radiation have biological effects whose intensity and relevance are, however, complex to predict a priori. The dose–response relationship of some of the radiation-induced changes is easy to determine, and follows a linear curve where a larger dose corresponds to greater damage (the so-called deterministic effects, including erythema, desquamation, cataracts, decreased white blood count, organ atrophy, fibrosis, and sterility). Most of these effects have a (individually variable) dose threshold. In contrast, the probability of the so-called stochastic effects increases with increasing dose, but their severity and clinical relevance are independent of the absorbed dose. These effects are more worrisome as they include cancer and genetic risk.

The dose to which medical operators are subject is generally not high enough to cause deterministic (direct) damage such as skin erythema/burns (which, however, may be observed—less rarely than normally believed by interventional cardiologists—in patients undergoing prolonged procedures in the catheterization laboratory). However, an increased incidence (up to 3.6% in addition to the 20% estimated current a priori risk) of certain types of neoplasms, including leukaemia and multiple myeloma or solid cancers of the thyroid, breast, bladder, colon, liver, lung, oesophagus, ovaries, brain, and stomach, has been reported.4 The assessment of the risk associated with radiation at low doses is however quite complicated, and failing to report exposure to other risk factors (for instance smoking) might have a larger effect than correctly reporting radiation exposure.

Although the mechanism of these phenomena is complex and incompletely understood, the production of reactive oxygen species triggered by ionizing radiation appears to play a central role. Reactive oxygen species may damage cell structures and, most importantly, DNA. In line with this hypothesis, studies by the group of Picano showed an increased prevalence of somatic mutations, as well as alterations in DNA repair genes, in interventional, as compared with non-interventional, cardiologists.57

Oxidative stress and apoptosis from X-ray exposure in interventional cardiologists

The same group of investigators have now expanded these observations, and demonstrate that professional exposure to low doses of radiation in a group of interventional cardiologists is associated with an increased bioavailability of reduced glutathione in erythrocytes and an intact total antioxidant capacity despite increased plasma hydrogen peroxide (a marker of oxyradical stress);8 in contrast, the concentrations of superoxide dismutase, another important cellular scavenger of oxygen free radicals, were significantly lower in interventionalists. The net result of these changes is that the bioavailability of reactive oxygen species was not different across groups. Thus, while interventionalists were subject to more radiation-induced oxidative stress (or, rather, response to radiation-induced stress), fortunately they developed (partial) counter-regulatory antioxidant defences. The authors also show an increased sensitivity to apoptosis both at baseline and in response to radiation.8 The biological and pathophysiological implications of these observations are complicated to interpret, and several limitations to the study need to be acknowledged. These include a small sample size, incomplete insight into the mechanisms (for instance, the lack of information on mitochondrial superoxide dismutase in other cell types, gene induction, susceptibility to apoptosis in response to reactive oxygen species) and consequences of the observations (what is the impact on endothelial function?). Further, the groups differed in terms of body mass index, which might be associated with oxidative stress, and information about the incidence of other cardiovascular risk factors is not provided. Despite these limitations, these data are interesting in that they might confirm the concept that low-dose radiation induces a protective phenotype.

Hormesis or harm?

The expression ‘radiation hormesis’ refers to the hypothesis that ionizing radiation, in doses that are just above the range of natural background levels, might produce beneficial effects, stimulating the activation of repair mechanisms that protect against disease (Figure 1). A number of compensatory and reparatory mechanisms are activated in response to the damage caused by ionizing radiation. These include up-regulation of antioxidant responses, activation of apoptosis (which scavenges damaged cells that may undergo tumorigenesis), activation of enzymatic DNA repair mechanisms, and activation of the immune system to help recognize mutated cells at risk of neoplastic transformation.9

Figure 1

There are several hypotheses on the nature of the dose–response curve between radiation exposure and cancer risk: the linear–no threshold model is based on the assumption that the risk of cancer is directly proportional to the dose level of ionizing radiation. In the exponential model, the risk of cancer increases exponentially with increasing exposure. In the hermetic model, low radiation doses actually have protective effects, while higher doses cause harm. Finally, in the stochastic model, the risk of cancer and radiation dose are not correlated.

These repair mechanisms would not only compensate the toxic effects of the small amount of ionizing radiation that triggered them, but might also prevent disease due to the exposure to other risk factors.9 There are a number of examples in nature of phenomena like hormesis: the most striking example might be ischaemic pre-conditioning, where exposure to short-term sublethal ischaemia reduces the damage associated with a more prolonged ischaemia: for instance, patients who refer to angina in the 24 h before an infarction have a much better prognosis as compared with those that do not.10

Interestingly, recent animal and human research has shown that a short-term, subtoxic production of reactive oxygen species (possibly such as that caused by low-dose radiation) has a central role in the mechanisms triggering ischaemic pre-conditioning.11 This short oxidative burst would trigger protective mechanisms, including up-regulation of antioxidant reserves, thus protecting from a more prolonged ischaemia. While the mechanisms of ischaemic pre-conditioning have been investigated in numerous studies, those triggered by radiation exposure are much less clear, but the analogies between these phenomena appear interesting and stimulating. Whether the above observations of Russo et al.8 reflect a protective ‘pre-conditioning-like’ phenomenon, as compared with a pathologically increased cellular ‘fragility’, is a more complex question that cannot be addressed with the evidence available at the moment. While reactive oxygen species are recognized to play a central role in cardiovascular disease, the pathophysiology of these phenomena is extremely complex (reviewed in Munzel et al.12 and in Gori and Munzel13), and hormesis/pre-conditioning and harm might be two sides of the same coin.

Whatever the answer, these considerations do not limit our responsibility towards patients, our colleagues, and ourselves, and we still need to aim at maintaining occupational radiation doses at levels ‘as low as reasonably achievable’.

Radiation exposure of the operator: how to limit it

Several guidelines have been prepared to address this issue.14 As a general rule, the simplest way to reduce operators' exposure is to reduce patients' exposure to radiation, which includes short operation times, use of low frame rates and of fluoro rather than cine, blind centring of the image, adequate collimation, and periodical maintenance of the X-ray instruments. The use of aprons and screens is compulsory, and that of shielded gloves and glasses would be useful. Regular monitoring using personal and environment dosimeters, care in maintaining a short distance between the intensifier and the patient's chest, and, since the intensity of radiation decreases exponentially with the distance between the source and target, the use of injection pumps, which allow the operator to stand back from the table and the intensifier, are important factors. Obviously, each operator has to rely on his/her own experience in balancing the benefit of protection devices with their impact on procedure duration (and total X-ray time). Furthermore, the angulation of the X-ray tube influences the amount of scatter radiation (Figure 2). While individual patient's anatomy (and operator's preferences) imply a certain degree of flexibility, choosing a fixed sequence of projections to be used for standard diagnostic procedures may significantly reduce radiation exposure and hazard. In general, LAO views >60° with cranial or caudal angulation >20° should be avoided as they are associated with 5- to 7-fold increases in radiation exposure.

Figure 2

Operator's radiation exposure for each angiographic view during cardiac catheterization. The duration of the runs obviously has an additional impact. In green, a proposed sequence of angiographic views that might be associated with reduced radiation exposure. Personal experience, and a patient's individual variations obviously may require changes to this scheme. Data from Kuon et al.15

In conclusion, more research is necessary, both at the level of basic science to understand the interaction between toxic (whether stochastic or linear) effects of ionizing radiation and hormesis phenomena, and at the level of epidemiology. While the effects of ionizing radiation remain incompletely understood, it is our responsibility as physicians to take all precautions in reducing any potential hazard to our patients, our colleagues, and ourselves. The beauty of modern medical images, the personal sense of self-achievement that follows a complex, prolonged interventional procedure, must be balanced by their costs, clinical utility, and risks—not least, that of prolonged operator exposure to radiation.

Acknowledgements

The authors would like to thank Dr A. Warnholtz for providing Figure 2.

Conflict of interest: none declared.

Footnotes

  • The opinions expressed in this article are not necessarily those of the Editors of the European Heart Journal or of the European Society of Cardiology.

References