Abstract
Individual factors can affect the risk of radiation-related cancer. This article presents the key findings of an ongoing systematic review in Task Group 111 on the modification of radiation cancer risk in animals, including the author's recent reports on rat breast cancer. The results indicate that early age at exposure is associated with a high risk of cancer in most organs, with some variability. For example, there is a peak of susceptibility during the peripubertal period regarding rat breast cancer. Females are more susceptible regarding the risk of all tumours. Smoking, diet-induced overweight, parity, hormones, chronic inflammation, and exposure to chemicals modify the risk of leukaemia and solid cancers in exposed animals. Radiation interacts with a high corn oil diet and mutagenic chemicals in supra-multiplicative and multiplicative manners, respectively, regarding breast cancer in rats. Genetic evidence indicates significant impacts of strain and genetic defects relevant to human tumour syndromes and DNA repair. There has been a reported quasi-multiplicative interaction with strain regarding rat breast cancer, as well as an increased risk associated with a Brca1 variant. These findings demonstrate diverse interactions between radiation and different modifiers, emphasising key areas for epidemiology and the integration of biology and epidemiology.
INTRODUCTION
Cancer risk is influenced by age and sex, as well as environmental and genetic factors. Epidemiology has attempted to characterise their impacts on radiation cancer risk, although the evidence is limited due to various difficulties. Animal studies complement epidemiology by identifying priority areas and adding cross-species and mechanistic perspectives. This proceeding article summarises some key findings from the currently ongoing systematic review in ICRP Task Group 111 regarding modification of radiation cancer risk in animals. Emphasis is put on available quantitative findings, but representative qualitative findings are also included. Note that references cited herein are not comprehensive due to space limitation.
KEY FINDINGS FROM ANIMAL STUDIES
Modification by age and sex
Evidence suggests that early age at exposure is generally associated with high risk (Castanera et al., 1971; Covelli et al., 1984; Anisimov and Prokudina, 1986; Sasaki and Fukuda, 2005). Some variability among organs exists, however, regarding the modification by age at exposure. For example, exposure at peripubertal age was the most potent in increasing breast cancer incidence in rats (Imaoka et al., 2023), supporting a recent epidemiologic finding (Brenner et al., 2018). Fetuses are not necessarily more susceptible than postnatal animals (Covelli et al., 1984; Benjamin et al., 1998; Sasaki, 1991; Sasaki and Fukuda, 2005), although it should be noted that some developmental events in human foetuses occur in postnatal mice (McCracken and Lorenz, 2001).
Attained age generally increases the excess absolute risk (EAR) and decreases the excess relative risk (ERR) in animals (Bruenger et al., 1991; Burns et al., 1993; Sasaki and Fukuda, 2005; Imaoka et al., 2023), consistent with the general trend observed in epidemiology (Grant et al., 2017).
Regarding sex, females are more susceptible regarding the risk of all tumours on both ERR (Chernyavskiy et al., 2017; Zander et al., 2020) and EAR bases (Grahn et al., 1992; Majo et al., 1996). Males are more susceptible to radiation-induced leukaemia (Ullrich and Storer, 1979; Majo et al., 1996). For other organs, evidence is either insufficient or not consistent.
Modification by lifestyle and environmental factors
Smoking and 239Pu inhalation show a supra-additive interaction (Mauderly et al., 2010). Diet-induced overweight increases leukaemia and solid cancers in exposed animals (Gross and Dreyfuss, 1986, 1990; Yoshida et al., 1997; Shang et al., 2014). Dietary corn oil shows a supra-multiplicative interaction with radiation in increasing breast cancer incidence in rats (Imaoka et al., 2023). Parity and hormones modify radiation-induced breast cancer and 90Sr-induced bone cancer (Nilsson, 1967; Nilsson and Ronnback, 1973; Bartstra et al., 1998; Takabatake et al., 2018). Chronic inflammation increases tumours in some radiation-induced models (Eulderink and van Rijssel, 1972; Hirose et al., 1976; Yoshida et al., 1993).
Exposure to carcinogenic chemicals generally puts additional cancer risk in animals exposed to radiation. Although only a small number of studies assess whether the interaction departs from additivity, the interactions seem to range from additivity to supra-additivity (Vesselinovitch et al., 1972; Peraino et al., 1986; Kakinuma et al., 2012; Iwata et al., 2013). Exposure to mutagenic chemicals shows a multiplicative interaction with radiation in increasing breast cancer incidence in rats (Imaoka et al., 2023). Some antioxidants and food components reduce radiation carcinogenesis (Grdina et al., 1991; Inano et al., 1999; Mitchell et al., 2012).
Modification by genetic factors
Evidence suggests considerable impacts of the strain and genetic defects relevant to human tumour syndromes and DNA repair in animals exposed to radiation, although the available evidence is mostly qualitative regarding whether the interaction is additive or multiplicative. It is noteworthy that studies using genetically modified animals sometimes omit either unexposed controls or wild-type controls. Available quantitative evidence suggests a quasi-multiplicative interaction between radiation/chemical exposure and strain difference on breast cancer incidence of rats (Nishimura et al., 2022). Some qualitative evidence implies that the interaction between radiation exposure and strain ranges from additivity to supra-additivity (Shellabarger et al., 1978; Ito et al., 1992).
Defects in non-homologous end joining repair via Prkdc mutations have positive or negative impacts on radiation-induced cancer depending on the tumour model (Ishii-Ohba et al., 2007; Haines et al., 2015; Tanori et al., 2019). Deficiencies in homologous recombination repair genes Rad54, Xrcc2, and Brca1 show a trend of elevating radiation-induced cancer (Jeng et al., 2007; Haines et al., 2015; Tanori et al., 2019; Nakamura et al., 2022). A high efficiency in DNA double-strand break repair (i.e., rate of decrease in the γ-H2AX foci), a strain-dependent phenotype in mice, is related to decreased incidence of lung tumour (Ochola et al., 2019). Many germline mutations related to human cancer syndromes increase the risk of radiation-induced cancer. Some qualitative evidence implies interactions between radiation exposure and mutations ranging from additivity to supra-additivity (Carlisle et al., 2010; Choi et al., 2012).
EXTRAPOLATION FROM ANIMALS TO HUMANS
Animal models are crucial for estimating radiation risk. However, due to the difference in the dose response between humans and animals, experimental evidence cannot be directly applied to humans. As part of the work of the Planning and Acting Network for Low Dose Radiation Research in Japan (PLANET) (Yamada et al., 2024), we used a multistage carcinogenesis model that assumes a mutational effect of radiation to gain cross-species insights from a mechanistic perspective. We analysed the cancer mortality data of Japanese atomic bomb survivors (Ozasa et al., 2012) and mouse experiments conducted in Japan (Sasaki, 1991). The analysis indicates that the difference in the radiation-related cancer mortality between humans and mice can be mainly attributed to the quantitative interspecies difference in spontaneous and radiation-induced mutation rates (Imaoka et al., 2024). This discovery may enhance the use of experimental evidence for predicting risks in humans.
CONCLUSIONS
These findings showcase heterogeneous interactions between radiation and various modifiers and highlight priority areas for epidemiology. Animal studies support that young age at exposure and female sex confer high radiation risk of all solid cancer, and male sex for leukaemia, providing findings consistent with epidemiology. Animal studies also suggest significant interaction between radiation and various lifestyle, environmental, and genetic factors on cancer risk, supporting a need for further research in humans. More rigorous analyses with biologically based models will delineate the mechanism underlying the species difference in the radiation-associated cancer risk and its modifications.