High Natural Background Radiation Areas: A Literature Review that Reveals Systematic Adaptive Response but Controversial Data With Single Dose

Abstract

The natural radiation background contributes to the dose of ionizing radiation received by the whole population. However, the telluric component of the natural background radiation is not homogenous on Earth: while the average effective dose has been estimated to be 2.4 mSv/year worldwide, certain regions are considered as high natural background radiation areas (HBRA). To investigate the specificities of a continuous exposure to low-dose-rate irradiation, we reviewed data of the major HBRA from 98 studies published between 1973 and 2023. Three conclusions were drawn: 1) the dose received by the HBRA inhabitants is much lower than values assessed on hot spots : at Ramsar (Iran), 260 mSv/year were assessed at the highest hotspots but the maximal estimated dose-rate received by inhabitants is 80 mSv/year; 2) when DNA or chromosome breaks, cancer or accelerated aging are used as endpoints, no significant difference was observed between cells from HBRA and non-HBRA inhabitants; 3) conversely, adaptive response effect was systematically observed on ex vivo lymphocytes from HBRA inhabitants when they are exposed to a high dose ranging for 0.25 to 4 Gy. A mechanistic model based on the radiation-induced nucleoshuttling of the ATM protein provides an explanation to these last two conclusions.

Introduction

The natural background radiation is composed of cosmic rays, (neutrons and other particles) telluric radioactivity (uranium and thorium daughters including radon gas) and radioactivity from living things (notably potassium-40 and carbon-14). Thus defined, the natural background radiation significantly contributes to the dose of ionizing radiation (IR) received daily by the whole population. ¹ In addition to the cosmic, telluric and the food and water components, a current increase of medical use of IR represents to date, mostly in developed countries, ¹ about 20% of dose in excess to be considered in the total population exposure. However, an essential radiobiological difference between medical exposure and natural background radiation is the dose-rate : while the doses received in the medical context are generally delivered at high dose-rate (higher than 2 Gy/min in radiotherapy; higher than 20 mGy/min in CT scan; higher than 2 mGy/min in mammography exams during a short time ² ), the natural background radiation consists in a low and continuous dose-rate of the order of nGy/min (here, the term “continuous” has been preferred to “chronic” since “chronic” may suggest some regular time intervals during which the exposure is nil).

While the cosmic component, that represents up to 20% of the contribution of the final dose, can be considered as constant, the telluric component of the natural background radiation is not homogenous on Earth: the calculated average effective dose is 2.4 mSv/year worldwide but certain regions are considered as high natural background radiation areas (HBRA). ³ This is notably the case of Ramsar (Iran), Kerala (India), or Changjiang (China).^4-6 In these HBRA, the dose-rate can reach up to 260 mSv/year at certain physical spots.^7,8 Let us remind that these values can exceed the annual dose limits authorized for workers (6 and 20 mSv/year for category B and A exposed workers, respectively). ⁹ We are however aware that it is difficult to compare natural background radiation doses with those that are received by workers since they are not delivered with the same scheme. However, in the Sievert system, both are based on the same principle of cumulation of the dose.

The exposure delivered at a very low and continuous dose-rate raises the question of the concomitance of the formation of radiation-induced (RI) DNA damage and the repair process. It also raises the question of a potential adaptive response through one or several generations and the potential risks of cancer or accelerated aging on exposed subpopulations. In order to investigate the molecular, cellular and clinical features that would be specific to these regions and to draw conclusions about the biological effects produced by low dose-rates, we have therefore surveyed the radiobiological data concerning the major HBRA from 98 studies published between 1973 and 2023.

For this review, an exhaustive literature search was conducted on PubMed web site, using a combination of keywords including “high background”, “HBRA”, “HLNRA”, “epidemiological studies”, “biomarkers”, “cancer”, “aging”, and “dosimetry”. Selected articles had to be published in peer-reviewed journals, focus on regions included in HBRA, and address the health consequences for people living in these areas or the radiobiological features observed in their cells. The articles were selected in two stages: an initial selection based on titles and abstracts, followed by a full reading of the articles selected to extract relevant information, such as the dosimetry of the region, the methods used, the biomarkers or epidemiological criteria studied, the sample analysis, and the results of the study, including their statistical significance. In a second step, collected data were organized into comparative table according to the above criteria (Table 1^3-6,8,10-102).

Table 1.

Summary of the Selected Publications Dealing With HBRA.

Reference	Authors and publication year	Title	HBRA	Endpoint
10	Movahedi et al, 2019	Association of telomere length with chronic exposure to ionizing radiation among inhabitants of natural high background radiation areas of Ramsar, Iran	Ramsar, Iran	Aging biomarkers
11	Das et al, 2012	No evidence of telomere length attrition in newborns from high level natural background radiation areas in Kerala coast, south west India	Kerala, India	Aging biomarkers
12	Das et al, 2009	Telomere length in human adults and high level natural background radiation	Kerala, India	Aging biomarkers
13	Saini et al, 2022	Evaluation of natural chronic low dose radiation exposure on telomere length and transcriptional response of shelterin complex in individuals residing in Kerala coast, India	Kerala, India	Aging biomarkers, DNA damage
14	Chen and Wei, 1991	Chromosome aberration, cancer mortality and hormetic phenomena among inhabitants in areas of high background radiation in China	China	Cytogenetics
15	Zakeri et al, 2011	Chromosome aberrations in peripheral blood lymphocytes of individuals living in high background radiation areas of Ramsar, Iran	Ramsar, Iran	Cytogenetics
16	Hayata et al, 2000	Chromosome translocation in residents of the high background radiation areas in southern China	China	Cytogenetics
17	Ramachandran et al, 2013	Cytogenetic studies on newborns from high and normal level natural radiation areas of Kerala in southwest coast of India	Kerala, India	Cytogenetics
18	Jiang et al, 2000	Dose-effect relationship of dicentric and ring chromosomes in lymphocytes of individuals living in the high background radiation areas in China	China	Cytogenetics
19	Hayata et al, 2004	Effect of high-level natural radiation on chromosomes of residents in southern China	China	Cytogenetics
20	Zhang et al, 2004	Effect of smoking on chromosomes compared with that of radiation in the residents of a high-background radiation area in China	China	Cytogenetics
21	Ahmad et al, 2013	Effects of chronic low level radiation in the population residing in the high level natural radiation area in Kerala, India: Employing heritable DNA mutation studies	Kerala, India	Cytogenetics
22	Balachandar et al, 2011	Evaluation of genetic alterations in inhabitants of a naturally high level background radiation and Kudankulam nuclear power project site in India	Odisha, India	Cytogenetics
23	Karuppasamy et al, 2018	Frequency of chromosome aberrations among adult male individuals from high and normal level natural radiation areas of Kerala in the southwest coast of India	Kerala, India	Cytogenetics
24	Cheriyan et al, 1999	Genetic monitoring of the human population from high-level natural radiation areas of Kerala on the southwest coast of India. II. Incidence of numerical and structural chromosomal aberrations in the lymphocytes of newborns	Kerala, India	Cytogenetics, epidemiology
25	Zhang et al, 2003	Imperceptible effect of radiation based on stable type chromosome aberrations accumulated in the lymphocytes of residents in the high background radiation area in China	China	Cytogenetics
26	Karuppasamy et al, 2016	Peripheral blood lymphocyte micronucleus frequencies in men from areas of Kerala, India, with high vs normal levels of natural background ionizing radiation	Kerala, India	Cytogenetics
27	Das et al, 2009	Spontaneous frequency of micronuclei among the newborns from high level natural radiation areas of Kerala in the southwest coast of India	Kerala, India	Cytogenetics
8	Mortazavi et al, 2005	Radioadaptive responses induced in lymphocytes of the inhabitants in Ramsar, Iran	Ramsar, Iran	Cytogenetics adaptative response
28	Ghiassi-Nejad et al, 2002	Very high background radiation areas of Ramsar, Iran: Preliminary biological studies	Ramsar, Iran	Cytogenetics adaptative response
29	Mohammadi et al, 2006	Adaptive response of blood lymphocytes of inhabitants residing in high background radiation areas of ramsar- micronuclei, apoptosis and comet assays	Ramsar, Iran	Cytogenetics adaptative response
30	Syaifudin et al, 2018	Micronucleus assay-based evaluation of radiosensitivity of lymphocytes among inhabitants living in high background Radiation area of Mamuju, West Sulawesi, Indonesia	Mamuju, Indonesia	Cytogenetics adaptative response
31	Ramachandran et al, 2017	Radio-adaptive response in peripheral blood lymphocytes of individuals residing in high-level natural radiation areas of Kerala in the southwest coast of India	Kerala, India	Cytogenetics adaptative response
32	Jain et al, 2016	Lack of increased DNA double-strand breaks in peripheral blood mononuclear cells of individuals from high level natural radiation areas of Kerala coast in India	Kerala, India	DNA damage
33	Jain et al, 2017	Efficient repair of DNA double strand breaks in individuals from high level natural radiation areas of Kerala coast, south-west India	Kerala, India	DNA damage protein expression adaptative response
34	Kumar et al, 2012	Evaluation of spontaneous DNA damage in lymphocytes of healthy adult individuals from high-level natural radiation areas of Kerala in India	Kerala, India	DNA damage protein expression adaptative response
35	Kumar et al, 2015	Effect of chronic low dose natural radiation in human peripheral blood mononuclear cells: Evaluation of DNA damage and repair using the alkaline comet assay	Kerala, India	DNA damage adaptative response
36	Masoomi et al, 2006	High background radiation areas of Ramsar in Iran: Evaluation of DNA damage by alkaline single cell gel electrophoresis (SCGE)	Ramsar, Iran	DNA damage adaptative response
37	Vivek Kumar et al, 2020	Premature chromosome condensation assay to study influence of high-level natural radiation on the initial DNA double strand break repair in human G0 lymphocytes	Kerala, India	DNA damage adaptative response
4	Tan et al, 2020	A model comparison of diffusion-controlled radon exhalation from solid and cavity walls with application to high background radiation areas	Changjiang, China	Dosimetry
38	Kardan et al, 2017	A national survey of natural radionuclides in soils and terrestrial radiation exposure in Iran	Iran	Dosimetry
39	Hosoda et al, 2021	A unique high natural background radiation area - dose assessment and perspectives	Indonesia	Dosimetry
40	Rostampour et al, 2012	An investigation of gamma background radiation in Hamadan province, Iran	Iran	Dosimetry
41	Gooniband et al, 2017	Analytical study of 226Ra activity concentration in market consuming foodstuffs of Ramsar, Iran	Ramsar, Iran	Dosimetry
42	Tavakoli et al, 2003	Annual radiation background in the city of Isfahan	Iran	Dosimetry
43	Matsuda et al, 2011	Background radiation and individual dosimetry in the costal area of Tamil Nadu, India	Tamil Nadu, India	Dosimetry
44	Amanat et al, 2013	Comparative measurements of radon concentration in soil using passive and active methods in high level natural Radiation area (HLNRA) of Ramsar	Ramsar, Iran	Dosimetry
45	Ramola et al, 2015	Comparative study of various techniques for environmental radon, thoron and progeny measurements	Odisha, India	Dosimetry
46	Mowlavi et al, 2009	Dose evaluation and measurement of radon concentration in some drinking water sources of the Ramsar region in Iran	Ramsar, Iran	Dosimetry
47	Morishima et al, 2000	Dose measurement, its distribution and individual external dose assessments of inhabitants in the high background radiation areas in China	China	Dosimetry
48	Ghiassi-Nejad et al, 2003	Exposure to (226)Ra from consumption of vegetables in the high level natural radiation area of Ramsar-Iran	Ramsar, Iran	Dosimetry
49	Veerasamy et al, 2021	Geochemical characterization of monazite sands based on rare earth elements, thorium and uranium from a natural high background radiation area in Tamil Nadu, India	Tamil Nadu, India	Dosimetry
50	Veerasamy et al, 2020	Geochemical behavior of uranium and thorium in sand and sandy soil samples from a natural high background radiation area of the Odisha coast, India	Odisha, India	Dosimetry
6	Ramola et al, 2012	Levels of thoron and progeny in high background radiation area of southeastern coast of Odisha, India	Odisha, India	Dosimetry
51	Shanthi et al, 2010	Measurement of activity concentration of natural radionuclides for the assessment of radiological indices	Kanyakumari, India	Dosimetry
52	Žunic et al, 2019	Measurement of uranium in urine, hair and nails in subjects of Niska Banja town, a high natural background radiation area of Serbia	Serbia	Dosimetry
53	Yuan et al, 2000	Measurements of Rn-222, Rn-220 and their decay products in the environmental air of the high background radiation areas in Yangjiang, China	Changjiang, China	Dosimetry
54	Haghani et al, 2013	Nanomaterial containing wall paints can increase radon concentration in houses located in radon prone areas	Ramsar, Iran	Dosimetry
55	Bavarnegin et al, 2013	Natural radionuclide and radiological assessment of building materials in high background radiation areas of Ramsar, Iran	Ramsar, Iran	Dosimetry
56	Pooya et al, 2015	Public exposure due to external gamma background radiation in boundary areas of Iran	Iran	Dosimetry
57	Fathabadi et al, 2019	Public ingestion exposure to 226Ra in Ramsar, Iran	Ramsar, Iran	Dosimetry
58	Fathabadi et al, 2017	Radioactivity levels in the mostly local foodstuff consumed by residents of the high level natural radiation areas of Ramsar, Iran	Ramsar, Iran	Dosimetry
59	Derin et al, 2012	Radionuclides and radiation indices of high background radiation area in Chavara-Neendakara placer deposits (Kerala, India)	Kerala, India	Dosimetry
5	Bavarnegin et al, 2013	Radon exhalation rate and natural radionuclide content in building materials of high background areas of Ramsar, Iran	Ramsar, Iran	Dosimetry
60	Dobrzyńsky et al, 2023	Radon-occurrence and impact on the health	NA	Dosimetry
61	Ramola and prasad, 2020	Significance of thoron measurements in indoor environment	Odisha, India	Dosimetry
62	Ziajahromi et al, 2014	Total effective dose equivalent assessment after exposure to high-level natural radiation using the RESRAD code	Ramsar, Iran	Dosimetry
63	Zha et al, 1996	Epidemiological survey in a high background radiation area in Yangjiang, China	Changjiang, China	Epidemiology
64	Zou et al, 2000	A case-control study of nasopharyngeal carcinoma in the high background radiation areas of Yangjiang, China	Changjiang, China	Epidemiology
65	Sutou, 2016	A message to Fukushima: Nothing to fear but fear itself	Multiple areas	Epidemiology
66	Nair et al, 2009	Background radiation and cancer incidence in Kerala, India-Karanagappally cohort study	Kerala, India	Epidemiology
67	Dobrzyńsky et al, 2015	Cancer mortality among people living in areas with various levels of natural background Radiation	Multiple areas	Epidemiology
68	Tao et al, 1999	[Cancer mortality in high background radiation area of Yangjiang, China, 1979-1995]	Changjiang, China	Epidemiology
69	Mortazavi et al, 2005	Cancer risk due to exposure to high levels of natural radon in the inhabitants of Ramsar, Iran	Ramsar, Iran	Epidemiology
70	Akiba et al, 2002	Child cancer risk in high-background radiation areas	Changjiang, China and Kerala, India	Epidemiology
71	Silva et al, 2021	Committed effective dose and lifetime cancer risk due to ingestion of natural radionuclides in grains grown in an area of high background radiation	Guarapari, Bresil	Epidemiology
72	Bhasin et al, 1980	Effect of natural background radiation on dermatoglyphic traits	Kerala, India	Epidemiology
73	Sudheer et al, 2022	Evaluation of risk due to chronic low dose ionizing radiation exposure on the birth prevalence of congenital heart diseases (CHD) among the newborns from high-level natural radiation areas of Kerala coast, India	Kerala, India	Epidemiology
74	Ahuja et al, 1973	Evaluation of effects of high natural background Radiation on some genetic traits in the inhabitants of monazite Belt in Kerala, India	Kerala, India	Epidemiology
75	Jaikrishan et al, 1999	Genetic monitoring of the human population from high-level natural radiation areas of Kerala on the southwest coast of India. I. Prevalence of congenital malformations in newborns	Kerala, India	Epidemiology
76	Zlobina et al, 2022	Impact of environmental Radiation on the incidence of cancer and birth defects in regions with high natural radioactivity	Russia	Epidemiology
77	Su et al, 2021	Lens opacity prevalence among the residents in high natural background radiation area in Yangjiang, China	Changjiang, China	Epidemiology
78	Pereira et al, 2021	Lifetime cancer risk increase due to consumption of some foods from a high background Radiation area	Guarapari, Bresil	Epidemiology
79	Saadat, 2003	No change in sex ratio in Ramsar (north of Iran) with high background of radiation	Ramsar, Iran	Epidemiology
80	Attar et al, 2007	Effect of high dose natural ionizing radiation on the immune system of the exposed residents of Ramsar town, Iran	Ramsar, Iran	Immune system
81	Talebian et al, 2020	Investigating the expression level of NF-KB and HIF1A genes among the inhabitants of two different background radiation areas in Ramsar, Iran	Ramsar, Iran	Immune system
82	Ghiassi-Nejad et al, 2004	Long-term immune and cytogenetic effects of high level natural radiation on Ramsar inhabitants in Iran	Ramsar, Iran	Immune system
83	Li et al, 2019	Long-term immune effects of high-level natural radiation on Yangjiang inhabitants in China	Changjiang, China	Immune system
84	Borzoueisil et al, 2013	The assessment of cytotoxic T cell and natural killer cells activity in residents of high and ordinary background radiation areas of Ramsar-Iran	Ramsar, Iran	Immune system
85	Borzoueisil et al, 2013	The effects of residence duration in high background radiation areas on immune surveillance	Ramsar, Iran	Immune system
86	Mortavazi et al, 2019	Is induction of anomalies in lymphocytes of the residents of high background Radiation areas associated with increased cancer risk?	Ramsar, Iran	Immune system epidemiology
87	Nishad et al, 2021	Chronic exposure of humans to high level natural background radiation leads to robust expression of protective stress response proteins	Kerala, India	Protein expression
88	Zakeri et al, 2012	Differential proteome analysis of a selected bacterial strain isolated from a high background radiation area in response to radium stress	Ramsar, Iran	Protein expression
89	Saini et al, 2020	Evaluation of the influence of chronic low-dose radiation on DNA repair gene polymorphisms [XRCC1, XRCC3, PRKDC (XRCC7), LIG1, NEIL1] in individuals from normal and high level natural radiation areas of Kerala coast	Kerala, India	Protein expression
90	Jain et al, 2017	Global transcriptome profile reveals abundance of DNA damage response and repair genes in individuals from high level natural radiation areas of Kerala coast	Kerala, India	Protein expression
91	Autsavapromporn et al, 2019	Identification of novel biomarkers for lung cancer risk in high levels of radon by proteomics: a Pilot study.	Thailand	Protein expression
92	Yamaguchi et al, 2022	Oxidative Modification Status of human serum albumin caused by chronic low-dose Radiation exposure in Mamuju, Sulawesi, Indonesia	Mamuju, Indonesia	Protein expression
93	Heidari et al, 2014	The effect of high level natural ionizing radiation on expression of PSA, CA19-9 and CEA tumor markers in blood serum of inhabitants of Ramsar, Iran	Ramsar, Iran	Protein expression
94	Bakhtiari et al, 2019	The expression of MLH1 and MSH2 genes among inhabitants of high background radiation area of Ramsar, Iran	Ramsar, Iran	Protein expression
95	Zhang et al, 2010	Mechanism study of adaptive response in high background radiation area of Yangjiang in China	Changjiang, China	Protein expression adaptative response
96	Nishad and Ghosh, 2018	Comparative proteomic analysis of human peripheral blood mononuclear cells indicates adaptive response to low-dose radiation in individuals from high background radiation areas of Kerala	Kerala, India	Protein expression adaptative response
97	Mortazavi et al, 2005	Apparent lack of radiation susceptibility among residents of the high background radiation area in Ramsar, Iran: can we relax our standards?	Ramsar, Iran	Risk estimation
98	Ghosh, 2022	Biological and cellular responses of humans to high-level natural radiation: A clarion call for a fresh perspective on the linear no-threshold paradigm	Multiple areas	Risk estimation
99	Nugraha et al, 2021	Comprehensive exposure assessments from the viewpoint of health in a unique high natural background radiation area, Mamuju, Indonesia	Mamuju, Indonesia	Risk estimation
3	Hendry et al, 2009	Human exposure to high natural background radiation: What can it teach us about radiation risks?	Multiple areas	Risk estimation
100	Abbasi et al, 2019	Martian residents: Mass Media and Ramsar high background Radiation areas	Ramsar, Iran	Risk estimation
101	Welsh et al, 2022	Ramsar, Iran, as a natural radiobiological Surrogate for Mars	Ramsar, Iran	Risk estimation
102	Mortazavi et al, 2005	The need for considering social, economic, and psychological factors in warning the general public from the possible risks due to residing in HLNRAs	Ramsar, Iran	Risk estimation

HBRA: Definitions and Average Dose Rates

We have analysed 98 peer-reviewed articles published in the 1973-2023 period. These papers revealed 6 major HBRA including Kerala (28% of reports), Ramsar (34%), and Changjiang (16%) (Table 1).

Ramsar (Iran)

Ramsar is a coastal city situated in northern Iran which is known to be the most irradiating residential area in the world (up to 260 mSv/year ¹⁰³ ). The origin of such high radiation background in this area is due to a high terrestrial concentration of Ra²²⁶ (up to 146 kBq/m³) and its decay products, such as Rn²²² (up to 160 kBq/m³), which were brought to the surface by the water from the hot springs. ¹⁰⁴ According to the studies carried out by the Atomic Energy Organization of Iran (AEOI), the radioactivity is likely due, on the one hand, to mineral water and, on the other hand, to travertine deposits, a kind of limestone deposed around hot springs, in which thorium is more abundant than uranium.^105,106 In some cases, local inhabitants used radium-enriched rocks from hot springs as building materials for their homes. Indoor radon levels in some habitations in Ramsar can reach 31 kBq/m³, which can be translated to average internal exposures of up to 71 mSv/year. However, there is a very large variability in doses and dose-rates received within this region. For example, dose-rates lower of 4 mSv/year or equal to 260 mSv/year can be assessed within a few hundred meters.^10,28 As a consequence, to estimate the doses received by the Ramsar region inhabitants, based on their occupations and their exact place of residence, is therefore particularly difficult and can vary greatly. For example, in the study carried out by Movahedi et al, in 2019, ¹⁰ two groups of individuals were considered: the HBRA1 group of individuals moderately exposed with annual dose rates of 4 to 8 mSv/year and the HBRA2 group of individuals highly exposed with annual dose rates of 8 to 80 mSv/year. These values are therefore very far from the maximum values of 260 mSv/year observed in some spots from ground measurements (Tables 1 and 2^{4–6,8,10–12,15–38,40,41,44–51,53,55–58,61–63,66,69–72,75,77–87,89,90,92–96,104,107–112}).

Table 2.

Summary of the Radiobiological Features of the Major HBRA.

HBRA	Ground measurements	Range of dose-rate received by inhabitants	References
Ramsar (Iran)	Up to 260 mSv/year	NHBRA a subset: <1.50 mSv/year HBRA subset: 1.51-80 mSv/year	5,8,10,15,28,29,36,38,40,41,44,46,48,55-58,62,69,79-82,84-86,93,94,104,107
Kerala (India)	Up to 80.98 mSv/year	NHBRA subset: <1.50 mSv/year HBRA subset: 1.51-45 mSv/year	11,12,17,21,23,24,26,27,31-35,37,66,70,72,75,87,89,90,96,108
Changyiang (China)	Up to 6.86 mSv/year	NHBRA subset: <1.5 mSv/year HBRA subset: 1.5 to 5.44 mSv/year	4,16,18-20,25,47,53,63,70,77,83,95,109,110
Guarapari (Brazil)	Up to 19 mSv/year		71,78
Mamuju (Indonesia)	Up to 115 mSv/year	HBRA subset from 1 study: mean of 6.15 mSv/year b	30,92,111
Other areas of India (Odisha and Tamil Nadu: South coast of India)	Up to 162.7 mSv/year	NHBRA subset: <1 mSv/year HBRA subset: Up to 13.88 mSv/year	6,22,45,49-51,61,112

^aNHBRA: non-HBRA.

^bFrom dosimetry calculations from internal exposure from food and water intakes.

Kerala (India)

The HBRA of coastal Kerala, situated in the southwest India, presents wide variation in dose and dose-rates (ranging from less than 1 to 45 mSv/year; average 4 mSv/year) and a large size of its population. The Kerala HBRA is a narrow coastal line stretching from Neendakara panchayat (Kollam district) in the south to Purakkad panchayat (Allapuzzha district) in the north. The reason for this high natural radiation background level is the presence of uneven distribution of monazite and other heavy minerals such as ilmenite, rutile, zircon, garnet, etc. Monazite contains approximately 9% Th²³² and 0.3% U²³⁸ in Kerala.^106,113 The great variability of doses received by the population is also found in biological studies. Considering that the “control” group gathers individuals receiving less than 1.5 mSv/year, like in Ramsar, 3 groups of exposed individuals are generally defined in Kerala: the HBRA1 group of individuals receiving from 1.5 to 5 mSv/year; the HBRA2 group of individuals receiving from 5 to 15 mSv/year and the HBRA3 group of individuals receiving more than 15 mSv/year.^{31,35,73,90,96} For example, in the study of Kumar et al, the average dose-rate received by the “HBRA1 group” was 2.69 mSv/year and varied from 1.07 to 5.55 mSv/year. In most of the studies concerning Kerala, the groups of individuals labeled “HBRA” do not receive more than 2.4 mSv/year, the world average value^1,114 (Tables 1 and 2).

Changjiang (China)

The Changjiang district is an administrative subdivision of the Jiangxi region situated at the east of China. There, the main sources of high-intensity natural background radiation are the nuclides of the decay products of Th²³² and U²³⁸ present in the environment. ¹⁶ The average exposure dose-rate is 5.88 mSv/year (maximum 6.86 mSv/year). ¹¹⁰ Once again, a large variability in annual doses exists inside this district depending on the natural concentrations of radionuclides in construction materials, the age of the buildings and the layout of houses in the hamlets. There was a fairly wide and heterogeneous distribution of indoor and outdoor environmental radiation. In one study, for example, indoor radiation doses due to exposure to natural radionuclides present in building materials may be approximately twice higher than outdoor ⁴⁷ and some studies consider the external exposure as well as the internal exposure, attributable to food and water intake. Thus, the annual dose varies drastically, depending on the age of the individuals and the season of the year. Indeed, since children and the elderly are more likely to stay indoors, the dose-rates are higher for these age groups. ⁴⁷ The annual dose-rates for the HBRA groups vary from 1.0 to 45 mSv/year and have been found much lower than the maximal physical measures of the hottest geological spots. ²³ Besides, the average dose received by the HBRA group individuals is very close to the average annual exposure worldwide (Tables 1 and 2).

Guarapari (Brazil)

The City of Guarapari, on the coast of Espırito Santo State, Brazil is also considered as an HBRA because of its soils naturally rich in monazite containing U²³⁸ and Th²³². According to the measurements performed at different points of this city in 2002, the average external exposure is 2.5 mSv/year but higher dose-rates, particularly assessed on the beach, are up to 19 mSv/year ¹¹⁵ (Tables 1 and 2).

Mamuju, Sulawesi (Indonesia)

In the Mamuju HBRA in Indonesia, recently discovered by the Indonesian National Nuclear Energy Agency (BATAN), the annual effective dose-rate ranges from 17 to 115 mSv/year, with an average of 32 mSv/year. This exposure is due to high concentrations of K⁴⁰, U²³⁸, Th²³² and Ra²²⁶ and Rn²²² their main radioactive decay products.^92,99 Calculation of cumulative lifetime dose suggests that Mamuju residents could receive up to 2.2 mSv/year on average (Tables 1 and 2).

Odisha (India)

The coastal area of Odisha, in eastern India is a well-known HBRA area rich in monazites and rutiles. High levels of radiation are caused by the presence of large amounts of naturally occurring radioactive material in rocks, soils, sands and water. Three radionuclides, ⁴⁰K, ²³⁸U, ²³²Th and their radioactive decay products, ²²⁶Ra and ²²²Rn, contribute significantly to these levels. ⁵⁰ The annual inhalation dose-rate in homes in Odisha due to radon and its progeny, as well as thoron and its progeny, ranges from 0.11 to 2.67 mSv/year, with an average from 0.93 mSv/year, and from 0.42 to 11.33 mSv/year, with an average of 2.39 mSv/year, respectively. ⁶¹ In another study, the gamma dose rate was also measured in the indoor and outdoor environment of the area by using a portable gamma dosimeter. The outdoor dose rate averaged 2.35 mSv/year with a maximum of 5.43 mSv/year and the indoor dose rate averaged 3.14 mSv/year with a maximum of 7.9 mSv/year ¹⁸ (Tables 1 and 2).

HBRA: Analysis of the Biological Studies

One of the first conclusions of the above literature analysis of dose-rates values was that the dose effectively received by the HBRA inhabitants is much lower than the values assessed on hot spots (Tables 1 and 2). This is notably true for Ramsar HBRA with more than 260 mSv/year assessed at the highest hotspots while the maximal estimated dose-rate received by Ramsar inhabitants is 80 mSv/year (for a small subset). In the 63 peer-reviewed articles dealing with the biological consequences of an exposure to IR in HBRA, several biomarkers were applied, notably cytogenetics (28%), DNA damage (10%), protein expression (9%), immune system biomarkers (11%), aging biomarker (6%) and epidemiology and cancer incidence (36%). Some of the studies deal with two or more biomarkers. Among these studies, 28% are about adaptive response and 72% involved a single dose (Figure 1).

Figure 1.

Relative Proportions of the Different Biomarkers Established in the 98 Peer-Reviews Analysed. (A) In Direct ex Vivo Cells Studies. (B) Adaptive Response Studies vs Direct ex Vivo Cells.

Cytogenetics

When chromosome aberrations or micronuclei are taken as endpoints, almost all studies (90%) did not reveal significant differences between the yield of cytogenetic events for HBRA and NHBRA individuals. Besides, the small subset of studies showing differences elicited discrepancies: all the conclusions drawn by the authors point to very small, rarely significant differences between the HBRA and NHBRA regions. For example, Ramachandran et al ¹⁷ showed no differences between the 27 295 studied newborns in Kerala HBRA and NHBRA areas, either through karyotype abnormalities or through the frequency of stable and unstable chromosomal aberrations. Considering micronuclei as endpoints, similarly, Das et al, ²⁷ and Karupassamy et al, ²⁶ did not observe any significant difference in basal micronuclei levels between newborns and the general population.

DNA Damage

When DNA damage were taken as endpoints, all studies showed generally the same amount of DNA strand breaks or less in cells derived from HBRA individuals than in NHBRA individuals. For example, by considering that immunofluorescence γH2AX foci reflects DNA double-strand breaks (DSB), Jain et al ³² showed a frequency of γH2AX foci equal to 0.078 ± 0.004 for HBRA inhabitants exposed to an average dose-rate of 11.04 ± 3.57 mSv/year, in comparison to the NHBRA population showing a frequency of 0.095 ± 0.009 γH2AX foci. ³²

Immune System Biomarkers

When biomarkers of immune system were taken as endpoints, the conclusions were not consensual, with some change in the proportions of all the blood cell types studied except for a decrease in the CD107a-positive cell population among the HBRA inhabitants. Other studies, such as Li et al, ⁸³ focusing on immune cell populations and biomarkers of inflammation, showed no difference among cell subtypes, to the exception of 5 markers of inflammation showing a slight increase (IFN-c, MCP-1, sIL-6R, EGFR, and CRP). ⁸³

Aging Biomarkers

All studies concerning the length of telomeres concluded that no aging effect was observed after exposure to IR in HBRA. Regarding aging biomarkers, molecular investigations were performed only the Ramsar region in Iran and the Kerala region in India. It is noteworthy that the dosimetry data of these regions in these studies is not systematically provided in all the reports. ⁹⁴ However, even though the methods of calculation or assessment of the dose were unequal among the selected studies, one can reasonably conclude that the exposure to IR in HBRA does not significantly accelerate aging effect.

Epidemiology and Cancer Incidence

Lastly, the great majority of reviewed studies did not show significant differences of cancer incidence between HBRA and NHBRA cohorts. In some epidemiological studies, researchers concluded to a decreased risk of leukemia-induced-death ⁷⁰ and a negative correlation between lung cancer and radon exposure. ⁶⁹ In addition to these negative correlations, which run against the fundamental assumption of an increased incidence of RI cancers or congenital malformations, several studies, such as Nair et al, ⁶⁶ or Jaikrishan et al, ⁷⁵ showed no correlation between cancer incidence or congenital malformations and exposure to IR in HBRA.

The Particular Case of Adaptive Response Experiments

The above analysis of the biological data suggests that there is no significant “HBRA effect” for a given cumulated dose received by ex vivo blood cells. However, 28% of the publications dealt with the adaptive response scenario that consisting in the succession of two IR doses, d and D separated by a period of time Δt, namely d Δt + D; with d < D).^116,117 In the present cases, d illustrates the priming dose received during exposure to IR in HBRA by HBRA inhabitants i.e. the cumulated dose that directly depends on the time of exposure in HBRA (or in non-HBRA inhabitants for controls). Besides, historically, the first report related to the adaptive response originated from experiments with a dose (d = 0.1-0.01 µCi/ml for 2-3 days) delivered with tritium contamination, i.e. equivalent to a low and continuous dose rate exposure followed by a challenging dose (D = 1.5 Gy X rays) applied to ex vivo cells at high dose-rate. ¹¹⁸ Like in the study of Olivieri et al, ¹¹⁸ the adaptive response experiments analyzed in the HBRA reports were based on a dose d delivered at low and continuous (HBRA) dose-rate, a negligible Δt period of time and a challenging dose D delivered at higher dose-rate. For the great majority of cases, the authors sampled ex vivo lymphocytes from HBRA inhabitants exposed to a dose d and thereafter applied the challenging dose D on lymphocytes in vitro (Figure 2).

Figure 2.

Schematic Illustration of the Induction of the DSB and the ATM Monomers according to the Irradiation Scenario. After a Single Dose D, a Certain Number of DSB are Induced and Thereafter Repaired as a Function of Time. In Parallel, a Certain Number of ATM Monomers are Induced From ATM Dimers, Diffuse to the Nucleus and Trigger the DSB Repair. In the Case of an Adaptive Response Scenario (d + Δt + D), DSB and ATM Monomers Induced by the Priming Dose d Cumulate with Those Directly Induced by the Challenging Dose D. In the Case of an Exposure to a Single Dose Delivered at Low-Dose Rate, DSB and ATM Monomers Result From the Accumulation of Infinitesimal Number of DSB and ATM Monomers Induced Daily. In the Case of an Adaptive Response Scenario with Priming Dose Delivered at Low-Dose Rate, Resulting in Cumulated Doses Delivered at Low Dose-Rate, DSB and ATM Monomers Result From the Accumulation of Infinitesimal Number of DSB and ATM Monomers Induced Daily Cumulate with Those Induced by the Challenging Dose D.

Interestingly, 100% of HBRA studies involving adaptive response scenario were found positive, with the challenging dose D ranging from 0.25 to 4 Gy (Table 1). For example, according to Mortazavi et al, ⁸ lymphocytes from HBRA inhabitants showed less chromosomal aberrations (0.111 ± 0.003) than the cells from non-HBRA inhabitants (0.167 ± 0.004) after a dose D of 2 Gy. Hence, while single dose experiments performed in HBRA provide controversial data, the fact that adaptive response experiments performed in HBRA were found systematically positive raises an important question of radiobiology that is discussed below.

Discussion

Dose-Rate Received by HBRA Inhabitants is Lower than Those Assessed at High Spots

One of the first conclusions of the literature review concerning HBRA data is that the average dose-rate received by the HBRA inhabitants is much lower than those assessed at the hottest spots. One of the most representative examples of such statement is the case of Ramsar in which some spots may reach 260 mSv/year while the most exposed subgroups received 80 mSv/year on average (Tables 1 and 2). It is important to remind that the effective dose is intended for radiological protection applications and is not actually a real dose, as is also the case for equivalent dose which is needed for evaluating effective dose. Thus, to a given effective dose related to natural background radiation exposure, corresponds a different absorbed dose for each organ of the body. It is therefore very important to rigorously mention the effective dose received by HBRA inhabitants in the reports to avoid any confusion between maximal values assessed and average dose calculated or assessed.

How to Explain the Difference Between Single-Dose and Adaptive Response Experiments Data?

The data analysis performed in this report suggests that there is no significant “HBRA effect” for a given cumulated dose received by ex vivo blood cells (single-dose experiment) while the adaptive response experiments from ex vivo blood cells of HBRA inhabitants exposed to a challenging dose were found positive.

To date, the number of the different types of RI DNA damage per Gy per cell is very well documented: in human untransformed quiescent fibroblasts but also on quiescent conjunctive cells, a dose of 1 Gy produces about 10000 base damage (BD), 1000 single-strand breaks (SSB) and 40 DNA double-strand breaks (DSB). If one considers that the body is composed of a great majority of quiescent conjunctive cells, and that the exposure is homogenous and made of gamma-rays, one can calculate the number of BD, SSB and DSB induced in the two representative conditions for all the cells of the body: 2.4 mSv/year (average worldwide dose-rate) and 80 mSv/year (highest average exposure assessed in Ramsar) (Table 3). The Table 3 provides the expected number of the different biochemical type of RI DNA damage: the corresponding absorbed dose would be so low that no significant yield of DNA damage is induced by natural background radiation, whatever the effective dose and the scenarios. Besides, even if the corresponding absorbed doses were calculated for a given tissue, the numbers of DNA damage induced per day would remain negligible. Consequently, it is not surprising that no “HBRA effect” was observed after a single dose among all the published reports analyzed in our review (Table 3).

Table 3.

Crude Estimates of the Number of DNA Damage and ATM Monomers Induced by IR in NHBRA and HBRA.

IR exposure scenario	BD/cell	SSB/cell	DSB/cell	ATM monomers produced for 24 h post-irradiation
Priming dose
2.4 mSv/year (average worldwide exposure)	24/year	2.4/year	0.096/year	112 000
80 mSv/year (maximal exposure at Ramsar)	800/year	80/year	3.19/year	3 106
Challenging dose
0.25 Gy	2500	250	10	8.4 107
2 Gy	20 000	2000	80	1.17 108
4 Gy	40 000	4000	160	1.28 108

With regard to the adaptive response scenarios, we have published in 2022 a paper that proposes a coherent biological interpretation of the adaptive response phenomenon from a model based on the RI nucleoshuttling of the ATM protein kinase (RIANS) model^116,117 (Figures 2 and 3). Such interpretation is not based on the DNA damage but on the ATM monomers induced by IR. Briefly, after exposure to IR, the cytoplasmic ATM dimers dissociate into ATM monomers that diffuse in the nucleus. Once in the nucleus, ATM monomers phosphorylate the X variant of the H2A histone protein (γH2AX), which triggers the recognition of the RI DSB by the non-homologous end-joining (NHEJ) pathway, the most predominant DSB signaling and repair pathway in humans.^119-121 However, the RIANS can be delayed by the overexpression of some cytoplasmic substrates of ATM (called X-proteins). These X-proteins hold SQ and TQ domains, specifically phosphorylated by ATM kinase after exposure to IR. ¹²² The X-proteins sequestrate the RI ATM monomers, decrease their flux in the nucleus and therefore affect the nuclear ATM kinase activity and the number of DSB recognized by NHEJ^121,123,124 (Figure 3). An overexpression of cytoplasmic X-proteins and a delayed RIANS may cause radiosensitivity, RI cancer or RI aging. ¹²⁵ For human radioresistant fibroblasts, about 40 DSB are induced per Gy per cell (the repair half-time of DSB is generally considered to be about 1 h). In the frame of the RIANS model, 10⁶ to 10⁸ ATM monomers are supposed to be emitted per Gy from cytoplasmic ATM dimers. The full ATM kinase activity is considered to be ensured for 24 h, at least. ¹²⁶ From these numerical values, one can deduce that, in the frame of the RIANS model, doses lower than 25 mGy do not induce DSB but still produce tens of thousands ATM monomers per cell, at least. Let’s take a representative example. In the frame of the RIANS model, N_diff, the number of ATM monomers that diffuse in the nucleus as a function of dose D and time-post-irradiation t obeys the following formula (1) for human radioresistant fibroblasts ⁶³ :

$${\mathrm{N}}_{\text{diff}}\left(\mathrm{t},\mathrm{D}\right)=\frac{\mathbf{SP}}{\mathbf{L}{\mathbf{\chi }}_{\mathbf{mono}}}\mathbf{ln}\left(\mathbf{1}+{\mathbf{\chi }}_{\mathbf{mono}}{\mathbf{I}}_{\mathbf{mono}}\mathbf{Dt}\right)$$ (1)

in which the nuclear membrane is characterized by a width L, a nucleus surface S, a permeability P and in which ${\mathrm{\chi }}_{\text{mono}}$ is defined as the ATM monomers reassociation coefficient and I_mono the number of IR-induced ATM monomers per Gy. By taking the numerical values validated in Bodgi and Foray (2016) ⁶³ from hundreds of human fibroblasts with different radiosensitivity, the formula (1) becomes, for a human radioresistant fibroblast:

$${\mathrm{N}}_{\text{diff}}\left(\mathrm{t},\mathrm{D}\right)=11048\hspace{0.17em}\mathrm{l}\mathrm{n}\left(1+1.5\hspace{0.17em}\text{Dt}\right)$$ (2)

Figure 3.

General Model for Adaptive Response Based on the RIANS Model. The Scenario d + Δt Produces a Significant Amount of Active ATM Monomers in the Nucleus before the Exposure to D. As a Result, More DSB are Recognized by Non-homologous End Joining (NHEJ) after d + Δt + D (Panel A) than after D (Panel B): Radiosensitivity and Radiosusceptibility Decrease. However, it is Noteworthy that Adaptive Response is Preferentially Observed in Radiosensitive (Group II) Cells. The Adaptive Response is Not Observed in Radioresistant (Group I) Cells since the Repair of DSB Induced by d + Δt is Complete.

The following conditions were taken: S/L = 100 π 10⁻⁶ and χ_mono I_mono = 1.5 for radioresistant cells. ⁶³ Hence, if N_tot (t, D) is defined as the total number of ATM monomers produced during a 24 h interval post-irradiation, N_tot (t, D) is given by the integral of N_diff (t,D):

$${\mathrm{N}}_{\text{tot}}\left(\mathrm{t},\mathrm{D}\right)={\int }_1^{1440}{\mathrm{N}}_{\text{diff}}\left(\mathrm{t},\mathrm{D}\right)\text{dt}$$ (3)

The numerical values obtained form this formula and shown in Table 3 confirmed that:

• - The numbers of the different biochemical type of DNA damage induced and remaining are negligible whether after an exposure to HBRA or to non-HBRA;

• - The quantity of ATM monomers accumulated in nucleus was found systematically much higher than the number of DNA damage;

• - When cells are exposed to HBRA, they provide a significant amount of ATM monomers (more than 10⁶ per day) that can help in recognizing more DSB when exposed to a challenging dose. Such additional flux of ATM monomers may represent some additional percents of ATM monomers to those produce directly by the challenging dose. After exposure to non- HBRA, such flux is negligible.

Interestingly, a recent study published by Bugala and Fornalski reached similar conclusions about the radiation adaptive response for constant dose-rate irradiation in HBRA from another mathematical model. ¹²⁷

Conclusions

The review of 98 studies published between 1973 and 2023 and dealing with HBRA suggest two conclusions: 1) the doses effectively received by the HBRA inhabitants are much lower than the values assessed on hot spots. This is notably true for Ramsar HBRA with more than 260 mSv/year assessed at the highest hotspots while the maximal estimated dose-rate received by Ramsar inhabitants is 80 mSv/year, which encourages authors to mention more precisely the dosimetry in the HBRA studies; 2) cells from HBRA inhabitants did not show consensual data when DNA damage, chromosome breaks, cancer or accelerated aging biomarkers were used as parameters; 3) a systematic adaptive response was observed in HBRA inhabitants when a second high dose was applied to ex vivo to lymphocytes. Indeed, the number of RI DNA damage appears to be too low to provide any significant “HBRA effect”. Conversely, HBRA exposures yield a significant and constant number of ATM monomers that may help cells in replying to additional doses. A mechanistic model based on the RI nucleoshuttling of the ATM proteins (the RIANS model) may provide an explanation for this last conclusion. Obviously, further experiments are needed to document the model proposed in this particular HBRA configuration.

ORCID iD

Nicolas Foray https://orcid.org/0000-0002-1282-1303