**1.2. Radiation metrics**

Biological effects of ionizing radiation are related to energy deposition in matter. To assess the impact of ionizing radiation on human health and to set guidelines in radioprotection, units to measure a dose and its biological effects are required.

The absorbed dose is defined as the amount of energy, originating from any type of ionizing radiation and any irradiation geometry that is absorbed per unit mass of material. The international SI unit for absorbed dose is gray (Gy). One Gy represents the absorption of 1 joule of energy in 1 kilogram of mass (1 J/kg). This definition is pure physical, as it does not consider the quality of the ionizing radiation type and the extent of biological damage it inflicts to certain tissues and/or organs. As a result, the terms equivalent dose and effective dose have been introduced [18].

The equivalent dose takes into account the ability of a particular kind of ionizing radiation to cause damage. It is obtained by multiplying the absorbed dose (Gy) with a radiationweighting factor (wR) attributed to each different radiation type (e.g., the wR of photons and electrons is 1, the wR of protons and charged ions is 2, and the wR of α particles and fission fragments is 20). The international SI unit for equivalent dose is the sievert (Sv) [18].

The effective dose is defined as the weighted sum of all tissue and organ equivalent doses multiplied by their respective tissue-weighting factor (wT). It expresses the biological effect that a certain type of ionizing radiation has on the human body. wT values have been defined to represent the contributions of individual organs and tissues to overall radiation effects on the human body. Similar to the equivalent dose, the effective dose has sievert (Sv) as international SI unit. Care should be taken with wT values because they constitute an average over both genders and adult ages to reflect the radiation burden to an average human adult [18, 19]. Examples of effective doses associated with different sources of ionizing radiation are presented in **Table 1**.

risk can be statistically evidenced for doses above 100 mGy. Nevertheless, doses below 100 mGy are inconclusive due to two practical limits of epidemiological studies: low statistical power that generates random errors and demography that gives rise to systematic errors. Due to a high natural incidence of cancer, a lifetime follow-up of larger cohorts would be needed to quantify excess cancer risks due to a low dose of ionizing radiation. This is practically infeasible. Furthermore, confounding factors, such as lifestyle risk factors for CVD, can hamper accuracy to confidently detect a small increase in cancer mortality (discussed in Section 2.4). Any inadequacy in matching between control and study groups may give rise to a bias that cannot be merely reduced by expanding the size of the groups [49]. As a consequence, risk assessment in the low-dose region (<100 mGy) is based on extrapolations made from high-dose risk estimates [50]. For cancer, it is widely accepted that the tumorigenic risk increases with radiation dose without the presence of a threshold (the stochastic linear nonthreshold [LNT] model). This assumption implies that no dose is absolutely safe, resulting in

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In contrast to cancer, non-cancer diseases have for long not been considered as health risks following exposure to low doses of ionizing radiation. Consequently, they were believed to have a threshold dose below which no significant adverse risks are induced (deterministic linear threshold model) [18, 53]. This idea has been challenged by epidemiological findings showing an excess risk of non-cancer diseases following exposure to doses lower than previously thought [34, 54]. Epidemiological evidence suggests an excess risk of CVD mortality above 0.5 Gy [34, 54]. For doses below 0.5 Gy, the dose-risk relationship is still unclear. However, if the relationship proves to be without a threshold, this may have a considerable impact on the current radiation protection system, since the overall excess mortality risk following low-dose

Current predictions indicate that in Western countries almost one of three people will develop cancer during their lifetime [56]. About 50–60% of all cancer patients will undergo radiotherapy with radiation doses averaging 1.8–2 Gy per fraction [57]. During the radiotherapeutic treatment of tumors located in the mediastinal region of the human body (breast, lung, and esophageal cancers), the heart and its blood vessels incidentally receive a part of the radiation dose [46]. Exposure of the cardiovascular system to these therapeutic doses is known to be associated with CVDs. The first epidemiological evidence of this association came from radiation-treated Hodgkin's lymphoma survivors in the 1960s. In a study of 258 Hodgkin's disease patients followed for a median of 14.2 years (range 0.7–26.2) after radiotherapy, cumulative risk for ischemic event increased from 6.4% (95% confidence interval (CI), 3.8 ± 10.7) at 10 years to 21.2% (95% CI, 15 ± 30) at 20–25 years after radiotherapy treatment. Risk for myocardial infarction was 3.4% (95% CI, 1.6 ± 7.0) at 10 years and 14.2% (95% CI, 9 ± 22) at 20–25 years, and risk for ischemic cardiac mortality was 2.6% (95% CI, 1.1 ± 6.1) at 10 years and 10.2% (95% CI, 5.3 ± 19) at 25 years (**Figure 2A**) [58]. Cardiac fibrosis, which causes cardiac dysfunction, arrhythmias, and heart failure, is also seen in Hodgkin's lymphoma survivors but is rather the result of the use of

implementation of the "as low as reasonably achievable" principle [51, 52].

exposure could double [55].

**2. Radiation-induced cardiovascular disease**

**2.1. Epidemiology of radiation-induced CVD**
