Non-cancer effects of radiation exposure: Cataracts,diseases of the circulatory system,and beyond

1. INTRODUCTION

For radiological protection purposes, the International Commission on Radiological Protection (ICRP) has classified non-cancer effects with a threshold-type dose–response relationship as tissue reactions (formerly, non-stochastic or deterministic effects), and equivalent dose limits aim to prevent the occurrence of such tissue reactions (Hamada and Fujimichi, 2014). Evidence has accumulated demonstrating that some non-cancer effects occur years or decades after exposure to ionising radiation at doses and dose rates much lower than previously considered. In 2011, ICRP recommended a nominal threshold of 0.5 Gy to the lens of the eye for cataracts and to the heart and brain for diseases of the circulatory system, independent of dose rate (ICRP, 2012). Research published since continues to provide updated knowledge (Hamada, 2023). This article gives an outline of recent developments in late-occurring non-cancer effects and considers the potential implications for radiological protection.

2. OCULAR DISEASES

For cataracts, Shore (2016) concluded that no influential epidemiological articles were published after the 2011 ICRP statement (ICRP, 2012) through early 2016. Since then, elevated risks below 0.5 Gy have been reported in several cohorts: e.g. following protracted exposure below 0.1 Gy in US radiological technologists (Little et al., 2018) or above 0.25 Gy in Russian Mayak workers (Azizova et al., 2018) and following chronic exposure at 0.1 Gy in the residents of the high natural background radiation area in China (Su et al., 2021). These studies support a lack of clear dose protraction effects consistent with ICRP's assumption to recommend the same threshold of 0.5 Gy independent of dose rate (ICRP, 2012). Any high value of dose threshold for cataract appears unlikely with long follow-up. On the other hand, if there is a threshold in the dose response, upward curvature is expected in a linear-quadratic model. Nevertheless, there was little or no evidence of linear-quadratic curvature in the studies that reported a threshold (Worgul et al., 2007; Neriishi et al., 2012). Such a discrepancy suggests methodological issues in inference on the threshold, and many other studies seem unlikely to have evaluated linear-quadratic curvature (Little, 2013). This necessitates further investigation.

Observations of similar risks of cataracts and cataract removal surgery and the lower threshold for cataract surgery than cataracts in Japanese atomic bomb survivors (Nakashima et al., 2006; Neriishi et al., 2007) led ICRP to judge the same threshold of 0.5 Gy independent of the severity of vision impairment, assuming progression of minor opacities into vision-impairing cataracts (ICRP, 2012). However, such an elevated risk for cataract surgery has not been confirmed in other cohorts, so uncertainties remain about the progressive nature of lenticular changes in particular after fractionated/protracted and chronic exposures to low doses.

A comprehensive evaluation of the overall effects of radiation on all ocular structures would be important. In this respect, elevated risks have been reported for normal-tension glaucoma (ocular, neurodegenerative disease) in atomic bomb survivors (Kiuchi et al., 2019) and Mayak workers (Azizova et al., 2022) and for diabetic retinopathy in atomic bomb survivors (Minamoto et al., 2004). Nonetheless, the long-held tenet that the lens is among the most radiosensitive ocular and body tissues appears to remain unchanged. Mechanisms behind the high radiosensitivity of the lens to low linear energy transfer (LET) radiation may involve abnormal proliferation and differentiation of lens epithelial cells, oxidative stress, and denaturation of lens proteins (Ainsbury et al., 2016, 2021), and additional mechanisms for high-LET radiation may include an oxygen effect, cell cycle dependence or high nitrogen content (Hamada and Sato, 2016).

3. DISEASES OF THE CIRCULATORY SYSTEM (DCS)

Elevated risks (especially for ischaemic heart disease and stroke) have been reported in various cohorts, in many with a mean dose of <0.2 Gy, and in various medically and occupationally exposed groups for doses <0.5 Gy (Little et al., 2021). In the Japanese atomic bomb survivors, a dose threshold was significant only for haemorrhagic stroke in females (Takahashi et al., 2012). Considering that other recent studies have not reported any significant thresholds in the dose–response relationship, the existence or otherwise of a threshold dose is unclear. It also remains unclear whether a threshold depends on time after exposure, whether severity increases with increasing dose, and whether DCS is attributable to the malfunction of populations of cells. There is the possibility that risk per unit dose is greater at lower doses and is not a simple function of dose rate (Little et al., 2020, 2023; Little and Hamada, 2022; Hamada et al., 2024).

The ICRP threshold dose is the same (0.5 Gy) for DCS and cataracts (ICRP, 2012), suggesting that the circulatory system can be as radiosensitive to low-LET radiation as the lens (although the excess relative risk per unit absorbed dose for DCS is much lower than that for cataracts), but may be much more resistant to high-LET radiation than the lens (Hamada, 2023: Sato et al., 2024). The underlying mechanisms for DCS are incompletely understood even at high doses, and targets remain unidentified (Tapio et al., 2021). Targets at the tissue or organ level may include the heart, large blood vessels (e.g. aorta and carotid), and kidneys. Targets at the cellular level (e.g. endothelial cells, cardiomyocytes, and myofibroblasts for the heart) may vary with DCS subtypes.

4. OTHER LATE-OCCURRING NON-CANCER EFFECTS

Increased radiation mortality risks were observed in atomic bomb survivors for non-cancer diseases of the respiratory system, the blood and blood-forming organs, and the circulatory system in both sexes and for those of the genitourinary system only in females (Ozasa et al., 2012), among which DCS is a major radiation health hazard of concern for non-cancer disease mortality from acute exposure.

There is growing evidence that occupational exposure in adulthood increases the risk of neurodegenerative diseases of the central nervous system (CNS) (e.g. Parkinson's disease, Alzheimer's disease, and dementia) (Azizova et al., 2020; Lopes et al., 2022; Srivastava et al., 2023; Dauer et al., 2024), although the impact of childhood exposure remains unknown.

5. FUTURE PERSPECTIVES

It remains open questions as to whether diverse tissue reactions with various degree of impacts on lethality, quality of life, etc. should all consistently be prevented with cumulative incidence risk of 1%, whether there is a need for a separate set of radiation weighting factors dedicated to absorbed dose limits to prevent tissue reactions, and whether such radiation weighting factors for tissue reactions should be the same for all tissue reaction outcomes for simplicity or differ with each outcome. Identification of potential factors (e.g. sex, age, lifestyle factors, co-exposures, comorbidities, genetics, and epigenetics) that may modify the radiation risk of cataracts and DCS would be important (Barnard and Hamada, 2023).

Cataracts, DCS, and other late-occurring non-cancer effects (e.g. normal-tension glaucoma and neurodegenerative diseases of the CNS) seem to deviate, with uncertainty in mechanism, from previously considered canonical tissue reactions with clear thresholds of relatively high dose. Given that a boundary between tissue reactions and stochastic effects is becoming weaker, the radiation effect classification system developed in 1977 (Hamada and Fujimichi, 2014) may need to be revisited for which more developments via continued studies in epidemiology, biology, and their integration would be of the utmost importance. For integration of epidemiology and biology, developments of biologically based dose–response (BBDR) models would be critical to enhance the risk assessment process, and determination of BBDR model parameters needs the adverse outcome pathway (AOP) approach (NCRP, 2020). Qualitative AOPs are under development for various non-cancer effects (Carrothers et al., 2024; Kozbenko et al., 2024; Sleiman et al., 2024).

6. CONCLUSIONS

Since ICRP Publication 1, ICRP has always considered that gonads, bone marrow, and the lens are among the most radiosensitive tissues (ICRP, 1959). Taking account of evidence for diverse non-cancer effects in various tissues, it remains the case that the lens is among the most radiosensitive tissues in the eye and in the body. Recent scientific developments tend to support the assumed lack of dose protraction effect, but the plausibility of the assumed progressive nature of lenticular changes awaits further studies. Accumulated evidence now suggests that the circulatory system is also radiosensitive, but its underpinning mechanisms are less clear. There is emerging evidence for other late-occurring non-cancer effects, such as normal-tension glaucoma and neurodegenerative diseases of the CNS. For more developments, continued studies in epidemiology, biology, and their integration would be important.