Radiation Protection Issues in Clinical Research Involving X-Ray Diagnostic Radiology Procedures

General Biological Effects of Ionising Radiation

Following Rontgen’s discovery of the X-ray in 1895, the adverse effects of these emanations were neither known nor thought of until clinical changes were observed, subsequently to be correctly attributed to the x-ray exposures. Clarence Dally, assistant to Thomas Edison, was recorded in 1896 to be using his wrist in an effort to perceive the heat generated by x-rays. Working with the rays led to erythema, hair loss and eventually to ulcerating wrist skin cancer; within eight years of working with x-rays he was dead. By 1911, over 90 cases had been documented. Moreover, radiologists from that time were noted to have a reduction in life expectancy and an increased incidence of leukaemia. Similar trends were noted in industries in were radioactive substances were being used [1]. From such experiences, it was later apparent that the changes were a result of the interactions of radiation with cells, rooted in their ability to ionise, creating chemical species (electrons, positive ions like H+ and free radicals), disrupting cellular water and cell chromosomes. Subsequent clinical features were noted to include focal inflammation and erythema changes, and eventually mitotic changes [9].

Large doses of radiation (>1Gy) will lead to cell interactions which may cause reduction in tissue cell division / multiplication. At reductions in the number of cells below a critical level, affected tissue/organ functions can be expected to be preserved. Above a critical cellular threshold, harmful changes lead to deterioration of organ/body function. These tissue effects, formerly known as deterministic, are now referred to as harmful tissue reactions, being likely to manifest at high radiation doses [1, 9].

Following exposure to low doses of radiation, stochastic effects result. The effects may be abnormal multiplication of cells leading to cancer and/or modification of cell chromosomal DNA genetics, leading to lethal or inheritable congenital abnormalities [1, 9].

Within the precautionary principle that assumes that any dose above background may cause harm, a radiation dose of 1mSv carries a relatively low cancer risk, at 1 in 10,000 [1]. Efforts to be more precise do not give consistent figures. In a 2001 study, British Radiologists were shown to be expressing lower cancer rates compared to estimates for those cases included within the Hiroshima and Nagasaki atomic bomb study [10]. In 2007, a large 15-country wide study [11] showed significant (p <0.002) excess relative risk (ERR) of 4.2 x 10-5 per mSv. The doses from Computed Tomography (CT) as used in diagnostic radiology are within the low dose (stochastic effect) range, a longitudinal study of the dose show a small but significant increased risk of malignancy, potentially also covering cumulative effects of previous exposures [12]. Despite these varying observations, the relatively low doses from CT examinations are seen to be associated with at least a small increase in cancer risk, albeit with stochastic effects in low-dose exposure remaining poorly understood [13, 14].

Clinical Situations

The human body cells, tissues and organs have varying features and susceptibility to ionising effects of irradiation. Cells that are actively dividing and immature or poorly differentiated are more radiosensitive. These facts partly explain the increased ionising radiation risks (harmful reactions and/or stochastic effects) in clinical entities like pregnancy, embryo/foetus, paediatrics, gonads, haematopoeitic system, gastrointestinal mucosa, neuro vasculature, breasts and thyroid gland [9].

In general, most radio-diagnostic activities are in the low- dose exposure range meaning that tissue harmful reactions are not expected. However, in fluoroscopic procedures (diagnostic and/or interventional, as in angiography) radiation harmful reactions may manifest [15].

Radiation risks (lifetime radiation-induced cancer as well as heritable effects) decrease with age for both males and females [14, 16]. In CT studies, women have been reported to have double the risk of radiation effects than men, believed to be associated with the radio-sensitivity of the female breast. Attempts to estimate the breast doses experimentally have resulted in widely varying results of 10-70 mGy. It is generally accepted that breast dose from CT is much greater than glandular tissue exposure in mammography. The risk is greatest for those who are in the less than 40 years of age group [12, 17].

Young age may have a compounding effect in pregnancy, stochastic risk being greater in the young and for females [16]. While a pregnant mother may well be considered to benefit from a particular diagnostic radiology exposure, the foetus is known to carry risks such as congenital malformation, mental retardation, and radiation-induced cancer, the risk being up to three-times greater than for adults [18]. Compared to more mature individuals, post-exposure to radiation the cells of paediatric patients typically have greater opportunity to undergo cancerous transformation, since these cells are dividing more rapidly than in adults [4, 14]. Immunological issues are equally important. Whether for low or high exposures, IR has a modifying and controlling influence on the cell contents, genes, cytokines, immunological cells, individual tissues and the organs [5, 6, 7]. Evidence from high exposure situations, such as in radiotherapy, cancer cells are known to elicit anti-tumour immune responses involving cell autonomous activities as well as intercellular communications. The late side effects from low radiation exposures have demonstrated radiation- induced cell-killing, bystander- (abscopal), inflammatory- and immunological effects. In a study reported by Nelson, et al. [5], exposure of rat ear cells to low doses of radiation caused a 30% and 10-15% reduction in adaptive immunity and blood cells respectively. With high radiation dose, the reductions were 70% and 65% respectively. Moreover, gene and cytokines expressions analysis of the radiated ear areas show increased chemo-attraction. These imply that immunological status decreases with increasing radiation dose and that lowered immunity situations may increase susceptibility to antigens following exposure to radiation [5]. Furthermore, these findings infer that ionising radiation immune modulation may result in positive or negative effects, depending on whether the patient has normal immune status or immunodeficiency (as for HIV or Covid 19 infected individuals) and if the IR enhances or depresses immunity.

Radiation Protection Aspects of Ethical Considerations

The Declaration of Helsinki, a World Medical Association document, contains the ethical principles of clinical research. Ethical assessment requires weighing risks against benefits. The researcher must also be aware of potential radiosensitivity of relevant tissue areas in the study [9, 19].

Unlike pharmaceutical and related studies, the agents having fairly well-known safe threshold doses below which effects are assumed zero, ionising radiation exposure have no known safe threshold, low ionising radiation dose included. This leads to importance in of incorporating radiation protection measures in each such study protocol [1, 18].

The ICRP 103 Recommendations [20] make it important to consider protection of research participants, facility radiation workers, also the public. These are considered under the three main components of justification, optimisation and dose limitation measures, well described by Martin and his group [1].

Regarding justification, there must be explanations supporting arguments for net benefit, needing to show that receipt of the radiation exposure outweighs potential harmful reactions and stochastic effects. The rationale for use of ionising radiation, without specific accompanying clinical use/indication must be discouraged and better still, disallowed. Where there are accompanying clinical indications for the radiation, the number of exposures must be guided by what is appropriate for clinical use, not by the research. The clinical need for any exposure and accompanying radiation dose must be estimated, realising that the potential cumulative effect of exposures carries increased risk [18, 21, 22]. In such respect, several ionising radiation articles in Dentomaxillofacial Radiology were commented upon in a 2013 editorial to the journal, one notably on the number of radiation exposures in a particular study, more than expected for the clinical use and as stated in the protocol [23].

As part of exposure dose optimisation, the number of participants must be limited to the minimum number required to meet the objectives of the study. Dose constrains must be employed by ensuring that none of the participants are also involved in ionising radiation exposure from other sources. Moreover, the principle of ALARA (As Low as Reasonably Achievable) must be employed. This is achieved by minimising the exposure time, where possible maximising distance from the source of exposure, maximising shielding of exposed areas, and minimising the quantity of radiation from the source [9].

Efforts must be made to limit the exposure to a limited relevant area by coning. Where critical organs lie close to the field of interest, the organ area must be shielded. The radiation generated from the source must not be more than that required for the purpose. Where fluoroscopy is involved, the operator must be mindful of potential tissue harmful reactions [15].

Workers in the ionising radiation study facility must also be protected and monitored to ensure that their exposures remain below 20 mSv per year (and < 100 mSv per five years). Members of the public (e.g. anyone accompanying participants) must be kept away from the study ionising radiation to ensure that dose incurred is limited to below 1 mSv per year [1, 24, 25].

To avoid accidental radiation during pregnancy, the 10- day rule must be observed (women of childbearing age must not be exposed to ionising radiation after the first 10 days from the beginning of menstruation). When it is necessary to expose a woman of child bearing age and the menstrual dates are uncertain, the pregnancy test (blood hCG) must be negative. For radiation protection reasons it is best to avoid exposure during pregnancy [3, 18, 26, 27].

Consent Process

In IR, the information provided about impact (especially when quantitative) is usually statistically derived, with associated uncertainty. This in turn affects the choice of language and efforts to ensure that research participants actually have a full understanding of the information [5, 12]. The willingness of any study individual to take part in a study must be preceded by provision of a detailed study Participant Information Sheet (PIS). To ensure that the PIS are understood by the participant, it must be written in very simple language, devoid of medical terminologies. Any unavoidable terminology must be fully explained [28]. Ideally, the study investigator or a professionally capable delegate of the study investigator must also fully explain the PIS to the participant. The contents of the PIS must include statements of voluntariness of consent, details of the study, duration, and number of participants, risks and plans to communicate findings after the study [5].

The main area of challenge is the accuracy of the assessment of radiation risk. This is because there are no empirically derived radiation risk figures. Protection of individuals participating in radiation research requires the consideration of all potential risks relating to ionising radiation. The available quoted risks are derived from statistic probabilities [8, 28, 29]. Accordingly, there is a considerable degree of uncertainty in the risk information provided to participants concerning radiation exposure. As a result of the uncertainties, there is no clear agreement on the nature and contents of information to be provided to participants.

The random nature of the effect of ionising radiation creates difficulty when trying to be specific on known effects of IR, low dose effects overwhelmingly being stochastic (i.e. random and probabilistic). In practice, the stochastic risks of IR exposures are difficult to demonstrate using empirical data, the risks being based on calculations and extrapolation from epidemiological data. Cumulative effects and radio sensitivity in women are greater than in men and for children they are more than for adults. The cumulative dose effects and individual sensitivity to radiation exposure are modifying factors in radiation risk estimation. This is compounded by the degree of risk that is socially accepted despite the potential harm. On balance, writing appropriate PIS is at the best highly challenging. The consent process in terms of description of possible effects and degree of likelihood are important but difficult to be ascertained with as mentioned there being no generally acceptable and consistent quantitative data. The sentences must be carefully constructed, not just in simplicity of the language but in the expression of the contents, to improve the understanding of the risk [28, 30].

Participant’s right must be respected. Scrutiny is affected by expertise of the ethics committee. It is essential, that no such study must be carried out without gaining favourable opinion/approval of an ethics committee. The study protocol must be detailed and be fully assessed by an ethics committee with advice from a clinical radiologist. The protocol must be scrutinised for input on radiation protection measures, where appropriate with pregnancy avoidance measures, ALARA exposures, immunological status, co-morbidity, and shielding of sensitive organs where possible.