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Evidence for beneficial low level radiation effects and radiation hormesis

Heinrich-Heine-University Düsseldorf, Germany and Brookhaven National Laboratory, Upton, NY, USA

Abstract

Low doses in the mGy range cause a dual effect on cellular DNA. One is a relatively low probability of DNA damage per energy deposition event and increases in proportion to the dose. At background exposures this damage to DNA is orders of magnitude lower than that from endogenous sources, such as reactive oxygen species. The other effect at comparable doses is adaptive protection against DNA damage from many, mainly endogenous, sources, depending on cell type, species and metabolism. Adaptive protection causes DNA damage prevention and repair and immune stimulation. It develops with a delay of hours, may last for days to months, decreases steadily at doses above about 100 mGy to 200 mGy and is not observed any more after acute exposures of more than about 500 mGy. Radiation-induced apoptosis and terminal cell differentiation also occur at higher doses and add to protection by reducing genomic instability and the number of mutated cells in tissues. At low doses reduction of damage from endogenous sources by adaptive protection maybe equal to or outweigh radiogenic damage induction. Thus, the linear-no-threshold (LNT) hypothesis for cancer risk is scientifically unfounded and appears to be invalid in favour of a threshold or hormesis. This is consistent with data both from animal studies and human epidemiological observations on low-dose induced cancer. The LNT hypothesis should be abandoned and be replaced by a hypothesis that is scientifically justified and causes less unreasonable fear and unnecessary expenditure.

Ionizing radiation and endogenous toxins at low doses

Everyone agrees that cellular responses to low values of absorbed doses of ionizing radiation are not readily predictable by extrapolation of responses observed at high doses. One reason for this unpredictability is in the physics of energy distribution in low-dose exposed tissues. For penetrating radiation, particle tracks arise stochastically throughout the exposed tissue with a relatively low density at low doses [1]. These tracks generate unevenly distributed ionizations and excitations of constituent molecules along the track path, as well as bursts of reactive oxygen species (ROS) [2]. In the case of exposure to internal emitters, the distribution of particle tracks is determined by the distribution of the emitter in tissue [3]. The lower the radiation fluence or number of particle emitters in a given tissue mass, the less crowded are the particles in the exposed mass and consequently the more heterogeneous is the distribution of ionized molecules and of ROS bursts.

The other reason stems from various biological confounding factors, especially the abundant and constant metabolic generation of ROS and of other endogenous toxins, on top of which low-dose radiation acts [4, 5]. The average production rate of endogenous DNA double strand breaks (DSB) per cell per day in the body is about 10³ times higher than that of radiogenic DSB from background irradiation. However, at low-LET (linear energy transfer) irradiation the probability of radiation induced DSB per primary DNA alteration of any type is about 10⁵ times higher than that caused endogenously [5].

Ratio of DNA damage and cancer probabilities

Radiation induced DNA damage and genomic instability increases with absorbed dose [2]. Such cellular effects come through direct energy deposition events from traversing particle tracks by which DNA damage rises proportional with dose. Depending on the amount of energy deposited per cell, bystander effects in non-irradiated neighbouring cells may add to this damage in tissue at low doses [6, 7]. By measuring damage in multicellular systems, values of damage per exposed cell or defined micromass are calculated averages. This implies that any bystander phenomenon that may have occurred is coregistered and expressed in the observed values. A dose of 1 mGy of low-LET radiation, such as 100 kVp X-rays, causes on average the following effects per potentially oncogenic stem cell with an average mass of 1 nanogram: 1 particle track; about 150 ROS; 2 DNA alterations of any kind; 10^–2 DSB; 10^–4 chromosomal aberrations; and the probability of an oncogenic transformation of the hit cell with lethal outcome is about 10^–13 to 10^–14 [8–10]. In other words, the ratio of the probabilities for radiation induced lethal cancer and the corresponding DSB is about 10^–11 to 10^–12. This means the statement that even one DSB poses a risk of causing a lethal cancer to develop from the affected cell is unreal and in fact, scientifically unfounded.

Adaptive responses, protection

A sudden suprabasal yet non-lethal rise of toxin concentration in a biological target tends to elicit stress responses and to stimulate adaptation, usually in terms of protective mechanisms in the sense of hormesis [11]. Increasing evidence in the literature over the past 25 years indicates that adaptive protection responses occur in mammalian cells in vivo and in vitro after single as well as protracted exposures to X- or -radiation at low doses (for reviews [5, 8–10, 12]). There appear to be two principal types of adaptive protection, one is to prevent and repair DNA damage and in doing so to keep cells alive and functioning properly. The other is to remove damaged cells from tissue by inducing apoptosis, terminal differentiation, and immune responses and thus to reduce genomic instability in the tissue system and eliminate mutated cells.

Contrary to the immediate initiation of repair after DNA damage has occurred, adaptive protection develops as a physiological stress response relatively slowly within a few hours and may last for several weeks to months. It reduces accumulation of DNA damage in tissue from many sources such as from metabolically generated or environmental toxins or renewed irradiation [13]. Protective responses occur in various ways. They appear to depend on mammalian species, individual genomes, cell types, cell cycle, and cell metabolism. Adaptive protection categories after single low-dose, low-LET irradiation, are as follows (for reviews [10, 14, 15]):

Damage prevention
Stimulation of detoxification of ROS appears to reach a maximum at about 4 h after irradiation and lasts for several hours or even weeks, depending on tissue and cell type. The process involves a rise of free glutathione and increased levels of superoxide dismutase (SOD) with decreased lipid peroxidation lasting for weeks in some tissues. This response accompanied a change in enzyme activities such as of thymidine kinase in mouse bone marrow in vivo to some 70% of control. Moreover, ROS detoxification has been linked to gene activation such as transcriptional regulation of the gamma-glutamylcysteine synthetase gene, predominantly through the AP-1 binding site in its promoter.

Damage repair
Protection against high-dose induced chromosomal aberrations and/or micronuclei formation in human lymphocytes and tissue culture cells increased to a maximum about 4 h after a conditioning low-dose of low-LET irradiation and lasted for about 3 days; the protection also operated against other DNA damaging agents. This protection covered up to about 30% of the damage seen in non-conditioned controls and varied between individuals and cell types; it was absent in some individuals and is probably determined genetically. This adaptive response probably involves a several-fold enhancement of the DNA repair rate. In human fibroblasts, micronuclei formation responded to conditioning doses from 1 mGy to 500 mGy equally effectively. At the lowest dose an energy-deposition event occurred in only about 40% of the cells and bystander effects may have been involved in causing the adaptive protection. Inhibition by a high dose of X-rays of DNA synthesis and cell growth in rat glial cells in culture was only about one quarter to one third at several hours following a conditioning low-dose exposure and this adaptive protection decreased with age of the donor rats. This response involved protein-kinase C (PCK), DNA-dependent protein-kinase (DNA-PK), and phosphatidylinositol 3-kinase (PI3K), as well as the activity of the ataxia-telangiectasia gene (ATM).

Damage removal by apoptosis
Damaged cells may be induced into apoptosis by intracellular and intercellular cellular signalling. Apoptosis may also occur within hours after high-dose irradiation. Low-dose induced apoptosis of pre-damaged cells with replacement by healthy cells may be a major route of in vivo removal of oncogenically transformed cells. Low-dose induced apoptosis is also assumed to operate through intercellular signalling from normal cells, which may also be activated by transformed cells in culture. Non-growing human fibroblasts in culture with DSBs from low-dose low-LET irradiation readily lost this damage to the level of DSBs in non-irradiated control cells after induction of proliferation; this damage removal was mainly due to apoptosis. Low-dose induced enhancement of DNA repair may be responsible for the observation in rat thymocytes, where the incidence of radiation-induced apoptosis first declined at low doses and only rose with higher doses. The induction of apoptosis apparently requires a certain level of DNA damage.

Stimulation of immune response
Removal of damaged cells occurred in vivo by way of a low-dose induced immune competence. This was, in another study, associated with a reduction in the incidence of cancer metastases to less than one third of control concomitantly with an increased number of circulating cytotoxic lymphocytes. Such response had its maximum in vivo at about 0.2 Gy. Low-dose induced immune competence may last for several weeks.

Protection and cell cycle
Damaged cells may also exit the system by premature differentiation and maturation to senescence. The various mechanisms of protection may be linked directly or indirectly to transient changes in the activity of the G₁ cell cycle checkpoint. Another mechanism in this category of damage removal is known to occur in a number of tissue culture cell types by way of hypersensitivity to low-dose radiation that disappears at higher doses. This hypersensitivity in some cells was linked to the cell cycle and disappeared in a number of cultured cells within about 4 h, but not immediately, after a single low-dose, low-LET irradiation. Radiation-induced predisposition to genetic instability in cultured cells also declined following low-dose irradiation. These data indicate prevention of damage removal by way of low-dose induced DNA repair.

Reduction of carcinogenesis
These protective responses, in one form or another, may be responsible for the observation of a reduction of spontaneously occurring cancers also through the action of bystander effects, in vivo as well as in vitro, where clonogenic transformation was the endpoint of observation. For instance, a single low dose low-LET irradiation of 2 month old mice heterozygous for the Trp-53 gene significantly delayed the appearance of "spontaneous" lymphoma and spinal osteosarcoma later in life. On the other hand, a review of tumour development following low-dose, low-LET irradiation in normal rodents showed the existence of a threshold dose. Several human epidemiological studies also indicate either a threshold or a reduced cancer incidence below control values following a single low-dose irradiation.

Low-dose induced changes in gene expression
The categories of adaptive protection listed above involved changes in gene expression. Thus, exposure of human skin fibroblasts in culture to a single dose of 20 mGy -radiation caused more than 100 genes to change their expression within 2 h. This gene group included stress response genes and was different from the group of genes in parallel cultures that concomitantly responded to 500 mGy. A similar pattern of expression amongst a total of 1574 genes developed with a delay of at least 30 min in -irradiated mouse brain, with 30% of the genes exclusively affected by 0.1 Gy. Moreover, human fibroblasts in culture showed DNA repair in the course of adaptive protection against micronucleus formation following acute high-dose irradiation; the repair was more effective in the gene-poor chromosome than in the gene-rich chromosome of the cells.

A common pattern

Despite the disparity of the systems examined and the responses, there appears to be a common pattern in the data. Adaptive protection following low doses of low-LET radiation appears to be the consequence of changed cellular signalling and to be ubiquitous. Adaptive protection is a physiological expression of cellular capabilities to maintain integrity of tissue structure and function in the face of various exposures to potentially toxic agents including ROS, whether from endogenous sources or from ionizing radiation [5, 16, 17]. One might speculate that DNA damage accumulation from any source eventually conditions a cell to become susceptible to apoptosis induced by low doses including that from background radiation exposure [4]. In this sense, background radiation exposure comes into focus as a possible trigger for maintaining tissue homeostasis.

Regarding their dependence on absorbed dose, the above listed categories of adaptive protection are summarized schematically in Figure 1. Except for apoptosis and terminal cell differentiation, all protective responses to single exposures tend to be expressed maximally after about 0.1 Gy and very little after more than about 0.5 Gy X- or -radiation [8, 18, 19]. Depending on type of adaptive protection in a given cell system, as summarized previously [5, 8–10, 14], in most mammalian cells so far examined, the expression of adaptive protection had a maximum above 5 mGy and below about 200 mGy.

View larger version (33K): [in this window] [in a new window]   Figure 1. Single low-dose induced adaptive responses have a protecting function through various mechanisms. Note that mechanisms of DNA damage prevention and repair and the immune stimulation decrease after a maximum at doses between 0.1 Gy and 0.2 Gy, in contrast to apoptosis incidence that increases with dose. Absorbed dose is in Gy and also in terms of microdosimetry, in that the mean energy deposition per particle traversal per defined micromass (specific energy ) (ICRU 1983) [1] is multiplied by the number of such events (NH) in the number of exposed micromasses (NE).

View larger version (28K): [in this window] [in a new window]   Figure 2. Single low-dose induced adaptive responses have different times of duration depending on protective mechanisms that begin with a delay of several hours and may last for days to weeks – and even up to months for immune response. Note that repair in response to radiation damage begins immediately after damage has occurred.

View larger version (44K): [in this window] [in a new window]   Figure 3. The dual effect of single low dose irradiation is schematically analysed according to a simplified model [10]. The net cancer risk derives from the difference between cancer induction through DNA damage and its prevention at the various dose levels (additional protection against damage accumulation from apoptosis is not shown here).

(1) Ionizing radiation causes DNA damage in mammalian cells proportional to the dose with additional possible bystander effects. (2) At background radiation exposure levels, DNA damage comes overwhelmingly from non-radiation sources. (3) The probability of radiation induced adaptive protection measurably outweighs that of damage from doses well below 200 mGy low-LET radiation. (4) The delayed and temporary adaptive protection at low doses involves damage prevention, damage repair and immune responses. They appear to operate primarily against DNA damage from non-radiation sources. Moreover, apoptosis and terminal cell differentiation also occur at higher doses and tend to remove susceptible damaged cells, as does the low-dose induced stimulation of the immune system. Cell removal reduces genomic instability and mutated cells from tissue. (5) At higher absorbed doses in tissue, cell and DNA damage appear increasingly to overrule, negate, or annihilate the more subtle signalling effects seen after low doses that lead to adaptive protection, whereas apoptosis and terminal cell differentiation continue to function. (6) The linear-dose-risk function appears invalid and should be replaced by a function that includes both linear and non-linear terms. Basic research data and human epidemiological data conform to a threshold or hormesis in the low-dose range.

Footnote

Owing to the limitation of space, it has not been possible to include a comprehensive list of references. A full list with text orientation may be obtained from the Editorial Office of the BJR.

Audience participation

The question put to the audience based on this contribution was "Does it appear reasonable to accept the experimental evidence of adaptive protection and the lack of epidemiological evidence of cancer following low dose exposure for the purpose of amending radiation protection recommendations?"

Responses: Yes 30%; no 52%; don't know 18%.

References

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