CR3 News Magazine 2023 VOL 1: JANUARY -- RADON REIMAGINED | Page 56

REVISED

Residential exposure to radon and DNA methylation across the lifecourse: an exploratory study in the ALSPAC birth cohort 

[version 2; peer review: 2 approved, 1 not approved]

REVISED Amendments from Version 1

In this manuscript version we have addressed all comments from the reviewers, and have made minor cosmetic changes to the manuscript text. In addition, we have added five additional references and we have added new analyses (available in 'Extended Data').

·         See the detailed response from the author(s) to the review by Mark  P.  Little

·         See the detailed response from the author(s) to the review by Rayjean J. Hung

·         See the detailed response from the author(s) to the review by Beata Peplonska

Introduction

Radon is a noble gas with no stable isotopes. Radon-222 (half-life (t1/2) 3.82 days)

and radon-220 (t1/2 55.2 seconds) are found in the environment as components of

the radioactive decay chains of the naturally occurring, long-lived radionuclides uranium-238 and thorium-232, respectively, which are found to varying extents in all rocks and soil. Radon-222 is the product of the decay of long-lived radium-226 (t1/2, 1600 years), and in most parts of the world, following their accumulation in enclosed spaces, inhalation of  222Rn and its short-lived radioactive decay products is the largest contribution of human exposure to ionising radiation. Globally, inhalation of  222Rn and its progeny is estimated to provide nearly half of the average annual effective dose (the radiation- and tissue-weighted whole-body absorbed dose) of 2.4 mSv from natural sources of ionising radiation1. However, the geographical variation of the effective

dose from  222Rn and its progeny is considerable, with a typical range of 0.2-10 mSv

per annum. The contribution to the global average annual effective dose from the inhalation of  220Rn and its progeny is much less at 0.1 mSv.

Radon-222 and some of its short-lived progeny deliver most of their radiation dose through short-range alpha-particle emission and, following inhalation, the radiation dose is received primarily by the bronchial epithelium from radon decay products. There is compelling epidemiological and experimental evidence that 222Rn and its decay products (hereafter, “radon”) cause lung cancer, with exposure-response associations approximately linear with no evidence of a threshold2,3, and radon has been classified as a Group 1 carcinogen (“carcinogenic to humans”) by the International Agency for Research on Cancer (IARC)4.

Exposure to radon is considered the second leading cause of lung cancer after tobacco smoking, and the principal cause in never-smokers5,6. The fraction of the lung cancer burden attributable to indoor exposure to radon ranges from 3% to 14% across the world, and is estimated at 3.3%7, or 1,100 lung cancer deaths annually, in the UK specifically3. Once inhaled, radon gas itself is mostly exhaled again, but a large proportion of the inhaled short-lived radon progeny deposits in the airways of the lungs with the alpha-particles emitted by 218Po and 214Po dominating the dose to the lung. In contrast, radon gas transported from the lung makes a larger contribution than its decay products to doses to organs/tissues other than the lung, particularly those with a comparatively high fat content (including the red bone marrow (RBM)). However, the evidence for radon causing cancers other than lung cancer is limited and relates to the fact that doses to other tissues from radon are relatively small. For example, the UK average annual equivalent dose (the radiation-weighted absorbed dose) to the RBM from radon is 80 µSv (children and adults) as compared to the RBM dose of 1430 µSv (5-year old) and 1070 µSv (adult) from all-natural sources8; this RBM equivalent dose from radon compares with that to the lung of 10,000 µSv.

Worldwide, the population-weighted geometric mean indoor level of radon activity concentration is estimated to be 30 Bq m-3 9, with a large geographical variation3. In England, the concentration in homes is about 20 Bq m-3 on average, but it ranges from 5 to 10,000 Bq m-3 and more in some radon-prone areas; for comparison, the average outdoor concentration is 4 Bq m-3 2. Variation between and within small geographical areas, as well as over time, can be the result of many factors including the abundance of 226Ra in the ground, fissuring of rocks, permeability of the soil, openings in the foundations of buildings through which radon can enter, and the extent to which a particular structure retains radon, including ventilation3,10. In Great Britain, a strong correlation between domestic radon levels and socio-economic status (SES) has been observed, where lower SES residences have, on average, only two-thirds of the radon levels of those of the more affluent, which may be related to greater underpressure in warmer and better-sealed houses11. Because people spend a significant portion of their time indoors, homes are typically the primary source of indoor radon exposure3, and within houses concentrations can also widely vary, with (in the USA) concentrations typically 50% higher in basements compared to the ground floor12.

The World Health Organisation (WHO) and International Commission on Radiological Protection (ICRP) recommend radon reference levels for homes in the range of 100-300 Bq m-3 13, with the ICRP reference level of 300 Bq m-3 having been incorporated as the upper limit for the reference level by the European Union14. The annual effective dose for a dwelling at 300 Bq m-3, and given several assumptions, is estimated at about 14 millisievert (mSv)15. In the UK, Public Health England recommends that indoor radon levels should be below 200 Bq m-3 (averaged over the home; the Action Level), which corresponds to about 12 mSv annual effective dose2, with 100 Bq m-3 being considered the Target Level for remediation work and for new buildings2.

The multistage carcinogenic process is in all probability a mixture of genetic and epigenetic processes. Ionizing radiation, in addition to producing mutations mainly by gene deletion and gross chromosomal damage, can also induce epigenetic effects4. Residential radon exposure has been associated with DNA-repair gene polymorphisms in adults (XpG gene Asp1104His, ADPRT gene Val762Ala, and NBS1 gene Glu185Gln polymorphisms)16 and partly replicated in children (XpD gene Lys751Gln, XpG gene Asp1104His and ADPRT gene Val762Ala polymorphisms)17, with the latter study also reporting double-strand break repair gene polymorphisms. Epigenetics describe heritable chemical modifications of DNA and chromatin affecting gene expression, and include DNA methylation, histone modifications and microRNAs which can act in concert to regulate gene expression18. In addition, the ‘bystander effect’, in which cells that are not directly irradiated, but are in the neighbourhood of cells that have, also exhibit phenotypic features of genomic instability that is considered to be epigenetic in nature4. DNA methylation is the most stable and most readily quantifiable epigenetic marker and is sensitive to pre- and post-natal exogenous influences19. Although the mechanisms of radiation-induced changes in DNA methylation remain largely unknown, the most plausible mechanism that has been proposed describes the effects of radiation on DNA methyltransferases20, while it has further been suggested that low dose radiation can increase DNA methylation at least in part through the generation of Reactive Oxygen Species (ROS)21,22. Ionising radiation exposure has been shown to affect DNA methylation in in vivo studies, and which has the potential to be transmitted via the germline to subsequent generations23,24. However, there is only limited data on effects of radon exposure on DNA methylation in humans, with some evidence from high exposed uranium miners in China25.

This study aims to explore whether there is evidence of DNA methylation from residential radon exposure in the general population and assesses whether any methylation varies across the lifecourse.

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