Low-dose Phenomenon Research Articles

An anomalous low dose phenomenon in gamma irradiated BaTiO3-based commercial multilayer ceramic capacitors

Owing to its miniaturization and high dielectric permittivity, BaTiO3-based multilayer ceramic capacitors (MLCCs) have attracted more and more attention in recent years, and are widely used in gamma-ray environments, such as nuclear and space application. Compared to the extensively studied thermal or electrical reliability issues, the potential risks caused by irradiation have not been well understood, let alone the dielectric structure changes. Unlike the common monotonic dose-dependent trend, we found non-monotonic results in MLCCs with low dose, named as the anomalous low dose (ALD) phenomenon. That is the capacitance decreases at low gamma-ray doses, and then abnormally recovers to the initial value at high doses. Similar cases have been found in almost all the physical properties of MLCCs. Intensive characterizations help to confirm that it is the dose-dependent consistent lattice and electronic structure changes that are most likely to cause this anomalous phenomenon. In detail, the gamma irradiation induces charged defects and consequently lattice distortion, which reduces the number of domains with low-field inversion and eventually causes the capacitance decrease. This work provides a new cognition about the gamma irradiation effect of BaTiO3-based (BTO) dielectrics and commercial MLCCs based on BTO.

Influence of the Hypersensitivity to Low Dose Phenomenon on the Tumor Response to Hypofractionated Stereotactic Body Radiation Therapy.

Stereotactic body radiation therapy (SBRT) has made the hypofractionation of high doses delivered in a few sessions more acceptable. While the benefits of hypofractionated SBRT have been attributed to additional vascular, immune effects, or specific cell deaths, a radiobiological and mechanistic model is still needed. By considering each session of SBRT, the dose is divided into hundreds of minibeams delivering some fractions of Gy. In such a dose range, the hypersensitivity to low dose (HRS) phenomenon can occur. HRS produces a biological effect equivalent to that produced by a dose 5-to-10 times higher. To examine whether HRS could contribute to enhancing radiation effects under SBRT conditions, we exposed tumor cells of different HRS statuses to SBRT. Four human HRS-positive and two HRS-negative tumor cell lines were exposed to different dose delivery modes: a single dose of 0.2 Gy, 2 Gy, 10 × 0.2 Gy, and a single dose of 2 Gy using a non-coplanar isocentric minibeams irradiation mode were delivered. Anti-γH2AX immunofluorescence, assessing DNA double-strand breaks (DSB), was applied. In the HRS-positive cells, the DSB produced by 10 × 0.2 Gy and 2 Gy, delivered by tens of minibeams, appeared to be more severe, and they provided more highly damaged cells than in the HRS-negative cells, suggesting that more severe DSB are induced in the "SBRT modes" conditions when HRS occurs in tumor. Each SBRT session can be viewed as hyperfractionated dose delivery by means of hundreds of low dose minibeams. Under current SBRT conditions (i.e., low dose per minibeam and not using ultra-high dose-rate), the response of HRS-positive tumors to SBRT may be enhanced significantly. Interestingly, similar conclusions were reached with HRS-positive and HRS-negative untransformed fibroblast cell lines, suggesting that the HRS phenomenon may also impact the risk of post-RT tissue overreactions.

Influence of Individual Radiosensitivity on the Hormesis Phenomenon: Toward a Mechanistic Explanation Based on the Nucleoshuttling of ATM Protein.

Hormesis is a low-dose phenomenon that has been reported to occur, to different extents, in animals, plants, and microorganisms. However, a review of the literature shows that only a few reports describe it in humans. Also, the diversity of experimental protocols and cellular models used makes deciphering the mechanisms of hormesis difficult. In humans, hormesis mostly appears in the 20 to 75 mGy dose range and in nontransformed, radioresistant cells. In a previous paper by Devic et al, a biological interpretation of the adaptive response (AR) phenomenon was proposed using our model that is based on the radiation-induced nucleoshuttling of the ATM protein (the RIANS model). Here, we showed that the 20 to 75 mGy dose range corresponds to a maximum amount of ATM monomers diffusing into the nucleus, while no DNA double-strand breaks is produced by radiation. These ATM monomers are suggested to help in recognizing and repairing spontaneous DNA breaks accumulated in cells and contribute to reductions in genomic instability and aging. The RIANS model also permitted the biological interpretation of hypersensitivity to low doses (HRS)—another low-dose phenomenon. Hence, for the first time to our knowledge, hormesis, AR, and HRS can be explained using the same unified molecular model.

L’énigme de l’interprétation biologique du modèle linéaire-quadratique enfin résolue ? Une synthèse pour les non-mathématiciens

The linear-quadratic (LQ) model is the only mathematical formula linking cellular survival and radiation dose that is sufficiently consensual to help radiation oncologists and radiobiologists in describing the radiation-induced events. However, this formula proposed in the 1970s and α and β parameters on which it is based remained without relevant biological meaning. From a collection of cutaneous fibroblasts with different radiosensitivity, built over 12 years by more than 50 French radiation oncologists, we recently pointed out that the ATM protein, major actor of the radiation response, diffuses from the cytoplasm to the nucleus after irradiation. The evidence of this nuclear shuttling of ATM allowed us to provide a biological interpretation of the LQ model in its mathematical features, validated by a hundred of radiosensitive cases. A mechanistic explanation of the radiosensitivity of syndromes caused by the mutation of cytoplasmic proteins and of the hypersensitivity to low-dose phenomenon has been proposed, as well. In this review, we present our resolution of the LQ model in the most didactic way.

Statistical modeling of the hormetic dose zone and the toxic potency completes the quantitative description of hormetic dose responses.

Quantifying the characteristics of hormesis provides valuable insights into this low-dose phenomenon and helps to display and capture its variability. A prerequisite to do so is a statistical procedure allowing quantification of general hormetic features, namely the maximum stimulatory response, the dose range of hormesis, and the distance from the maximum stimulation to the dose where hormesis disappears. Applying extensions of a hormetic dose-response model that is well-established in plant biology provides a direct estimation of several quantities, except the hormetic dose range. Another dose range that is difficult to model directly is the distance between the dose where hormesis disappears and the dose giving 50% inhibition, known as toxic potency. The present study presents 2 further model extensions allowing for a direct quantification of the hormetic dose range and the toxic potency. Based on this, a 4-step mathematical modeling approach is demonstrated to quantify various dose-response quantities, to compare these quantities among treatments, and to interrelate hormesis features. Practical challenges are exemplified, and possible remedies are identified. The software code to perform the analysis is provided as Supplemental Data to simplify adoption of the modeling procedure. Because numerous patterns of hormesis are observed in various sciences, it is clear that the proposed approach cannot cope with all patterns; however, it should be possible to analyze a great range of hormesis patterns.

The low-dose phenomenon: How bystander effects, genomic instability, and adaptive responses could transform cancer-risk models

From the atomic bomb dropped over Japan to nuclear accidents at Three Mile Island, Chernobyl, and the Fukushima Daiichi Nuclear Power Station, there is strong public demand for information on the cancer risks from radiation exposure. In this article, the author explores some of the biological phenomenon that could alter or confirm current concepts of low-dose effects. Reviewing bystander effects, adaptive responses, and genomic instability, the author writes that these phenomena could revolutionize conventional understanding of how to approach cancer risk assessments in low-dose, possibly protracted, environments. Though current consensus supports a linear no-threshold model, evidence suggests that these biological responses just may overturn that thinking.

DNA-PKcs and ATM influence generation of ionizing radiation-induced bystander signals

The phenomenon by which irradiated cells influence non-irradiated neighboring cells, referred to as the bystander effect (BSE), is not well understood in terms of the underlying pathways involved. We sought to enlighten connections between DNA damage repair and the BSE. Utilizing sister chromatid exchange (SCE) frequencies as a marker of the BSE, we performed cell transfer strategies that enabled us to distinguish between generation versus reception of a bystander signal. We find that DNA-dependent Protein Kinase catalytic subunit (DNA-PKcs) and Ataxia Telangectasia Mutated (ATM) are necessary for the generation of such a bystander signal in normal human cells following gamma (gamma)-ray exposure, but are not required for its reception. Importantly, we also show that directly irradiated human cells do not respond to receipt of a bystander signal, helping to explain why the BSE is a low-dose phenomenon. These studies provide the first evidence for a role of the DNA damage response proteins DNA-PKcs and ATM specifically in the generation of a bystander signal and intercellular signaling.

Differential activation of signalling factors following low and high dose of gamma radiation in vivo

The activation of signalling molecules that contribute to the development of radioresistance following radiotherapy was investigated following irradiation with very low doses (0.1 and 0.5 Gy) and high dose (1 and 3 Gy) of γ radiation. Expression of protein kinase C (PKC) was isoform specific. There was a marked difference in the response of ERK 44/42, which is known to confer radioresistance on the tumour cell. The expression at low dose was persistent till 24 hrs with a reappearance at 7 days, while the response at high dose (3 Gy) was transient, an activation at 4 hrs with a return to normal values at the subsequent time periods. These studies indicate that data obtained at high doses should not be extrapolated to low doses. The response of each signalling factor is different at different doses. Since radioadaptation and the development of radioresistance is a low dose phenomenon, ERK 44/42 seems to be the most relevant among the signalling factors.

Alternative Models for Low Dose-Response Analysis of Biochemical and Immunological Endpoints for Tetrachlorodibenzo- p-dioxin

As part of the current reassessment of dioxin, the empirical relationships between administered tetrachlorodibenzo- p-dioxin and selected immune and biochemical endpoints were investigated. A dose-response analysis from the published literature was performed using Linear, Sigmoid- E max and Power Law functions. The results of this analysis indicate that the use of a wide dose range may bias the interpretation of low-dose phenomenon. The Power Law function was applied exclusively to low-dose subsets enabling estimation of dose response in the low-dose range. Subsequently, high-dose data were fit using Power Law subset analysis. This approach resulted in a change in slope value from low- to high-dose subsets for thymic atrophy, immune suppression, benzo( a)pyrene hydroxylase activity, and ethoxyresorufin- o-deethylase activity. This change suggests that there is a high probability that there is a tissue concentration along the dose-response continuum which results in biological activity from low to high dose. This analysis also demonstrates that, the Power Law functional fit to the low-dose data differs quantitatively from the fit to the high-dose data for several noncancer endpoints. Therefore, by using the Power Law function a more accurate and biologically relevant assessment of risk can be produced for noncancer endpoints.