Histone H2AX phosphorylation on a serine four residues from the carboxyl terminus (producing gammaH2AX) is a sensitive marker for DNA double-strand breaks (DSBs). DSBs may lead to cancer but, paradoxically, are also used to kill cancer cells. Using gammaH2AX detection to determine the extent of DSB induction may help to detect precancerous cells, to stage cancers, to monitor the effectiveness of cancer therapies and to develop novel anticancer drugs.

γH2AX and cancer

The carcinogenic risk induced by low doses of ionizing radiation is controversial. It cannot be assessed with epidemiologic methods alone because at low doses the data are imprecise and often conflicting. Since the 1970s, the radiation protection community has estimated the risk of low doses by means of extrapolation from the risk assessed at high doses, generally by using the linear no-threshold (LNT) model.

The LNT relationship implies proportionality between dose and cancer risk. This approach is based on one set of data and two hypotheses: (a) The relationship between dose and DNA damage in vivo seems linear from 1 mGy to 100 Gy with use of H2AX foci as a marker for DNA double-strand breaks (DSBs)—however, this marker is not specific (1); (b) each DSB is hypothesized to have the same probability of inducing cell transformation, irrespective of the quantity of DSBs present simultaneously in the cell; and (c) each transformed cell is hypothesized to have the same probability of developing into an invasive cancer, irrespective of the dose delivered to the tissue. The advances during the past 2 decades in radiation biology, the understanding of carcinogenesis, and the discovery of defenses against carcinogenesis challenge the LNT model, which appears obsolete (2–6).

Life developed in a bath of ionizing radiation and solar ultraviolet radiation and created aerobic organisms requiring (a) defenses against the metabolically induced reactive oxygen species, (b) DNA repair, and (c) elimination of damaged cells. Several sets of data show the efficacy of these defenses to be much higher at low than at high doses and for fractionated or protracted irradiation than for acute irradiation.

The LNT model was introduced as a concept to facilitate radiation protection (7). But the use of this model led to the claim that even the smallest dose (one electron traversing a cell) may initiate carcinogenesis—for instance, from diagnostic x-ray sources (8,9). This claim is highly hypothetical and has resulted in medical, economic, and other societal harm.

The French Academies report (10) concluded that the LNT model and its use for assessing the risks associated with low doses are not based on scientific evidence. In contrast, the Biological Effects of Ionizing Radiation (BEIR) VII report (11) and that of the International Commission on Radiological Protection (ICRP) (12) recommended the use of the LNT model. We wish to update this debate by using recent radiation biologic and epidemiologic data.

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The linear no-threshold relationship is inconsistent with radiation biologic and experimental data.

Natural radiation is the major source of human exposure to ionising radiation, and its largest contributing component to effective dose arises from inhalation of 222Rn and its radioactive progeny. However, despite extensive knowledge of radiation risks gained through epidemiologic investigations and mechanistic considerations, the health effects of chronic low-level radiation exposure are still poorly understood. The present paper reviews the possible contribution of studies of populations living in high natural background radiation (HNBR) areas (Guarapari, Brazil; Kerala, India; Ramsar, Iran; Yangjiang, China), including radon-prone areas, to low dose risk estimation. Much of the direct information about risk related to HNBR comes from case–control studies of radon and lung cancer, which provide convincing evidence of an association between long-term protracted radiation exposures in the general population and disease incidence. The success of these studies is mainly due to the careful organ dose reconstruction (with relatively high doses to the lung), and to the fact that large-scale collaborative studies have been conducted to maximise the statistical power and to ensure the systematic collection of information on potential confounding factors. In contrast, studies in other (non-radon) HNBR areas have provided little information, relying mainly on ecological designs and very rough effective dose categorisations. Recent steps taken in China and India to establish cohorts for follow-up and to conduct nested case–control studies may provide useful information about risks in the future, provided that careful organ dose reconstruction is possible and information is collected on potential confounding factors.

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Human exposure to high natural background radiation: what can it teach us about radiation risks?

Precise detection of low-dose X- and γ-radiations remains a challenge and is particularly important for studying biological effects under low-dose ionizing radiation, safety control in medical radiation treatment, survey of environmental radiation background, and monitoring cosmic radiations. We report here a photoluminescent uranium organic framework, whose photoluminescence intensity can be accurately correlated with the exposure dose of X- or γ-radiations. This allows for precise and instant detection of ionizing radiations down to the level of 10−4 Gy, representing a significant improvement on the detection limit of approximately two orders of magnitude, compared to other chemical dosimeters reported up to now. The electron paramagnetic resonance analysis suggests that with the exposure to radiations, the carbonyl double bonds break affording oxo-radicals that can be stabilized within the conjugated uranium oxalate-carboxylate sheet. This gives rise to a substantially enhanced equatorial bonding of the uranyl(VI) ions as elucidated by the single-crystal structure of the γ-ray irradiated material, and subsequently leads to a very effective photoluminescence quenching through phonon-assisted relaxation. The quenched sample can be easily recovered by heating, enabling recycled detection for multiple runs.

Highly Sensitive Detection of Ionizing Radiations by a Photoluminescent Uranyl Organic Framework

We present a wide variety of experimental data indicating that linear no-threshold theory (LNT) greatly exaggerates the cancer risk from low level radiation LNT is based on cancer initiating hits on DNA molecules, but many other factors affect the progression from DNA damage to a fatal tumor, such as availability of DNA repair enzymes, immune response, and cell suicide Data are presented to show that these are generally stimulated by low level radiation (LLR) and suppressed by high doses that serve as calibrations for LNT Since the great majority of cancers are caused by natural chemical processes, the protection against these provided by LLR may make LLR beneficial rather than harmful Genes turned on and turned off by LLR are often different from those affected by high doses Direct studies of cancer risk vs dose are reviewed: animal experiments generally indicate that LNT exaggerates the risk of low level radiation, and the same is true of most data on humans except possibly where dose rates are very high Data show that the time delay between receipt of dose and cancer death increases with decreasing dose, which means that, with low level radiation, death from natural causes will often occur first This implies an effective threshold Responses to this type of information by various official and prestigious groups charged with estimating cancer risks from radiation are reviewed

The Cancer Risk from Low Level Radiation

People in some areas of Ramsar, a city in northern Iran, receive an annual radiation absorbed dose from background radiation that is up to 260 mSv y−1, substantially higher than the 20 mSv y−1 that is permitted for radiation workers. Inhabitants of Ramsar have lived for many generations in these hig

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Very high background radiation areas of Ramsar, Iran: preliminary biological studies.

It has been reported that on reaching a certain level of cell damage the production of repair enzymes is triggered which decreases the chromosome aberrations If this happens, prolonged exposure to high levels of natural radiation in areas with elevated levels of background radiation could decrease the frequency of chromosome aberrations Recent epidemiological studies indicated that there is an increased risk of cancer in healthy individuals with high levels of chromosomal aberrations Studies performed in Nordic countries as well as Italy, showed that increased levels of chromosome aberrations in lymphocytes can be used to predict cancer risk in humans One may conclude that a dose of ionising radiation sufficient to produce a certain level of cell damage increases production of antioxidants and repair enzymes that decrease either the frequency of chromosome aberrations or the cancer risk People in some areas of Ramsar, a city in northern Iran, receive an annual radiation dose from background radiation that is more than five times higher than the 20 mSv Yr-1 that is permitted for radiation workers Inhabitants of Ramsar have lived for many generations in these high background areas If an annual radiation dose of a few hundred mSv is detrimental to health, causing genetic abnormalities or an increased risk of cancer, it should be evident in these people The absorbed dose rate in some high background radiation areas of Ramsar is approximately 55-200 times higher than that of the average global dose rate It has been reported that 3–8% of all cancers are caused by current levels of ionising radiation If this estimation were true, all the inhabitants of such an area with extraordinary elevated levels of natural radiation would have died of cancer Our cytogenetic studies show no significant differences between people in the high background area compared to people in normal background areas As there was no increased level of chromosome aberrations, it may be predicted that the cancer incidence is not higher than in the neighbouring areas with a normal background radiation level Although there is not yet solid epidemiological information, most local physicians in Ramsar report anecdotally that there is no increase in the incidence rates of cancer or leukemia in their area There are no data to indicate a significant increase of cancer incidence in other high background radiation areas (HBRAs) Furthermore, several studies show a significant decrease of cancer death rates in areas with high backgrounds It can be concluded that prolonged exposure to high levels of natural radiation possibly triggers processes such as the production of antioxidants and repair enzymes, which decreases the frequency of chromosome aberrations and the cancer incidence rate

Cancer incidence in areas with elevated levels of natural radiation

It has been estimated that exposure to unpredictable extremely large solar particle events would kill the astronauts without massive shielding in interplanetary space. The high LET component of space radiation, neutrons especially, makes the major contribution to the genetic risks. Recent findings concerning the induction of adaptive response by neutrons and high cumulative doses of gamma radiation in human cells have opened a new horizon for possible implications of radiation adaptive response in human. Screening the candidates of long-term space missions by in vitro adaptive response studies help to identify the individuals with low radiation susceptibility and high radioadaptive response. In these selected individuals, chronic exposure to elevated levels of space radiation during a long-term mission can considerably decrease their radiation susceptibility and protect them against the unpredictable exposure to relatively high radiation levels caused by solar activity.

S.M.J. Mortazavi

Papers

Very high background radiation areas of Ramsar, Iran: preliminary biological studies.

Cancer incidence in areas with elevated levels of natural radiation

The life saving role of radioadaptive responses in long-term interplanetary space journeys