A Revised System of Radiological Protection Is Needed.

ABSTRACT: The system of radiological protection has been based on linear no-threshold theory and related dose-response models for health detriment (in part related to cancer induction) by ionizing radiation exposure for almost 70 y. The indicated system unintentionally promotes radiation phobia, which has harmed many in relationship to the Fukushima nuclear accident evacuations and led to some abortions following the Chernobyl nuclear accident. Linear no-threshold model users (mainly epidemiologists) imply that they can reliably assess the cancer excess relative risk (likely none) associated with tens or hundreds of nanogray (nGy) radiation doses to an organ (e.g., bone marrow); for 1,000 nGy, the excess relative risk is 1,000 times larger than that for 1 nGy. They are currently permitted this unscientific view (ignoring evolution-related natural defenses) because of the misinforming procedures used in data analyses of which many radiation experts are not aware. One such procedure is the intentional and unscientific vanishing of the excess relative risk uncertainty as radiation dose decreases toward assigned dose zero (for natural background radiation exposure). The main focus of this forum article is on correcting the serious error of discarding risk uncertainty and the impact of the correction. The result is that the last defense of the current system of radiological protection relying on linear no-threshold theory (i.e., epidemiologic studies implied findings of harm from very low doses) goes away. A revised system is therefore needed.

Modeling Cell Survival Fraction and Other Dose-Response Relationships for Immunodeficient C.B-17 SCID Mice Exposed to 320-kV X Rays.

US homeland security concerns related to potential misuse of γ-ray-emitting radiation sources employed in radiobiological research (eg, shielded cesium-137 irradiators) led to recommendations by the National Research Council to conduct studies into possibly replacing γ-ray irradiators used in research involving small rodent and other models with X-ray instruments. A limiting factor is suitability of the X-ray photon energy spectra. The objective of our research was to demonstrate the suitability of the radiation energy spectrum of 320-kV X rays after filtration (HVL = 4 mm Cu) for in-vivo cytotoxicity studies in immunodeficient C.B-17 SCID mice. By using a previously-published Hazard Function (HF) model to characterize dose-response relationships for in vivo bone marrow and spleen cell survival fractions and also to characterize the acute lethality risk (hematopoietic syndrome mode) we demonstrate that the filtered 320-kV X-ray beam appears suitable for such studies. A key finding for C.B-17 SCID mice when compared to results previously obtained for immunocompetent C.B-17 mice is that the immunodeficient mice appear to be more radioresistant, implicating a possible role of the immune system capacity in radiosensitivity of mammals.

Epidemiologic Studies Cannot Reveal the True Shape of the Dose-Response Relationship for Radon-Induced Lung Cancer.

A long-standing controversy is the correct shape of the dose-response relationship for lung cancer induction by inhaled radon (eg, residential radon) at low levels. A probabilistic approach is used in this commentary to show that cohort and case-control epidemiologic studies cannot reveal the true shape of the dose-response relationship for radon-induced lung cancer. Using the indicated approach, it is found that while the dose response for radon-induced lung cancer is expected to be threshold-increasing, the dose-response curve for the cancer incidence when cancers caused by smoking and other carcinogens are included is expected to be threshold-decreasing (ie, threshold-hormetic), as low-level radon can protect from cancer induction by other carcinogens via stimulating the body's natural defenses against cancer. These defenses include DNA damage repair, removal of aberrant cells via apoptosis, suppression of cancer promoting inflammation, and anticancer immunity.

The LNT model for cancer induction is not supported by radiobiological data.

The hallmarks of cancer have been the focus of much research and have influenced the development of risk models for radiation-induced cancer. However, natural defenses against cancer, which constitute the hallmarks of cancer prevention, have largely been neglected in developing cancer risk models. These natural defenses are enhanced by low doses and dose rates of ionizing radiation, which has aided in the continuation of human life over many generations. Our natural defenses operate at the molecular, cellular, tissue, and whole-body levels and include epigenetically regulated (epiregulated) DNA damage repair and antioxidant production, selective p53-independent apoptosis of aberrant cells (e.g. neoplastically transformed and tumor cells), suppression of cancer-promoting inflammation, and anticancer immunity (both innate and adaptive components). This publication reviews the scientific bases for the indicated cancer-preventing natural defenses and evaluates their implication for assessing cancer risk after exposure to low radiation doses and dose rates. Based on the extensive radiobiological evidence reviewed, it is concluded that the linear-no-threshold (LNT) model (which ignores natural defenses against cancer), as it relates to cancer risk from ionizing radiation, is highly implausible. Plausible models include dose-threshold and hormetic models. More research is needed to establish when a given model (threshold, hormetic, or other) applies to a given low-dose-radiation exposure scenario.

A Critique of Recent Epidemiologic Studies of Cancer Mortality Among Nuclear Workers.

Current justification by linear no-threshold (LNT) cancer risk model advocates for its use in low-dose radiation risk assessment is now mainly based on results from flawed and unreliable epidemiologic studies that manufacture small risk increases (ie, phantom risks). Four such studies of nuclear workers, essentially carried out by the same group of epidemiologists, are critiqued in this article. Three of the studies that forcibly applied the LNT model (inappropriate null hypothesis) to cancer mortality data and implicated increased mortality risk from any radiation exposure, no matter how small the dose, are demonstrated to manufacture risk increases for doses up to 100 mSv (or 100 mGy). In a study where risk reduction (hormetic effect/adaptive response) was implicated for nuclear workers, it was assumed by the researchers to relate to a "strong healthy worker effect" with no consideration of the possibility that low radiation doses may help prevent cancer mortality (which is consistent with findings from basic radiobiological research). It was found with basic research that while large radiation doses suppress our multiple natural defenses (barriers) against cancer, these barriers are enhanced by low radiation doses, thereby decreasing cancer risk, essentially rendering the LNT model to be inconsistent with the data.

Effect of internal contamination with tritiated water on the neoplastic colonies in the lungs, innate anti-tumour reactions, cytokine profile, and haematopoietic system in radioresistant and radiosensitive mice.

Tritium is a potentially significant source of internal radiation exposure which, at high levels, can be carcinogenic. We evaluated whether single intraperitoneal injection of BALB/c and C57BL/6 mice with tritiated water (HTO) leading to exposure to low (0.01 or 0.1 Gy) and intermediate (1.0 Gy) cumulative whole-body doses of ß radiation is immunosuppressive, as judged by enhancement of artificial tumour metastases, functioning of NK lymphocytes and macrophages, circulating cytokine's levels, and numbers of bone marrow, spleen, and peripheral blood cells. We demonstrate that internal contamination of radiosensitive BALB/c and radioresistant C57BL/6 mice with HTO at all the absorbed doses tested did not affect the development of neoplastic colonies in the lungs caused by intravenous injection of syngeneic cancer cells. However, internal exposure of BALB/c and C57BL/6 mice to 0.1 and 0.01 Gy of ß radiation, respectively, up-regulated cytotoxic activity of and IFN-γ synthesis in NK lymphocytes and boosted macrophage secretion of nitric oxide. Internal contamination with HTO did not affect the serum levels of pro- (IL-1ß, IL-2, IL-6, TNF-α,) and anti-inflammatory (IL-1Ra, IL-4, IL-10) cytokines. In addition, exposure of mice of both strains to low and intermediate doses from the tritium-emitted ß-particles did not result in any significant changes in the numbers of bone marrow, spleen, and peripheral blood cells. Overall, our data indicate that internal tritium contamination of both radiosensitive and radioresistant mice leading to low and intermediate absorbed ß-radiation doses is not immunosuppressive but may enhance some but not all components of anticancer immunity.

Radiation-hormesis phenotypes, the related mechanisms and implications for disease prevention and therapy.

Humans are continuously exposed to ionizing radiation throughout life from natural sources that include cosmic, solar, and terrestrial. Much harsher natural radiation and chemical environments existed during our planet's early years. Mammals survived the harsher environments via evolutionarily-conserved gifts ̶ a continuously evolving system of stress-induced natural protective measures (i.e., activated natural protection [ANP]). The current protective system is differentially activated by stochastic (i.e., variable) low-radiation-dose thresholds and when optimally activated in mammals includes antioxidants, DNA damage repair, p53-related apoptosis of severely-damaged cells, reactive-oxygen-species (ROS)/reactive-nitrogen-species (RNS)- and cytokine-regulated auxiliary apoptosis that selectively removes aberrant cells (e.g., precancerous cells), suppression of disease promoting inflammation, and immunity against cancer cells. The intercellular-signaling-based protective system is regulated at least in part via epigenetic reprogramming of adaptive-response genes. When the system is optimally activated, it protects against cancer and some other diseases, thereby leading to hormetic phenotypes (e.g., reduced disease incidence to below the baseline level; reduced pain from inflammation-related problems). Here, some expressed radiation hormesis phenotypes and related mechanisms are discussed along with their implications for disease prevention and therapy.

Commentary: ethical issues of current health-protection policies on low-dose ionizing radiation.

The linear no-threshold (LNT) model of ionizing-radiation-induced cancer is based on the assumption that every radiation dose increment constitutes increased cancer risk for humans. The risk is hypothesized to increase linearly as the total dose increases. While this model is the basis for radiation safety regulations, its scientific validity has been questioned and debated for many decades. The recent memorandum of the International Commission on Radiological Protection admits that the LNT-model predictions at low doses are "speculative, unproven, undetectable and 'phantom'." Moreover, numerous experimental, ecological, and epidemiological studies show that low doses of sparsely-ionizing or sparsely-ionizing plus highly-ionizing radiation may be beneficial to human health (hormesis/adaptive response). The present LNT-model-based regulations impose excessive costs on the society. For example, the median-cost medical program is 5000 times more cost-efficient in saving lives than controlling radiation emissions. There are also lives lost: e.g., following Fukushima accident, more than 1000 disaster-related yet non-radiogenic premature deaths were officially registered among the population evacuated due to radiation concerns. Additional negative impacts of LNT-model-inspired radiophobia include: refusal of some patients to undergo potentially life-saving medical imaging; discouragement of the study of low-dose radiation therapies; motivation for radiological terrorism and promotion of nuclear proliferation.

First generation stochastic gene episilencing (step1) model and applications to in vitro carcinogen exposure.

A novel first-generation stochastic gene episilencing (STEP1) model is introduced for quantitatively characterizing the probability of in vitro epigenetically silencing (episilencing) specific tumor-suppressor-microRNA (miRNA) genes by carcinogen exposure. Although the focus is mainly on in-vitro exposure of human cells to ionizing radiation, the mathematical formulations presented are general and can be applied to other carcinogens. With the STEP1 model, a fraction fj of the surviving target cells can have their tumor-suppressor-miRNA gene of type j silenced while the remaining fraction, 1 - fj , of the surviving cells do not undergo gene episilencing. Suppressor gene episilencing is assumed to arise as a Poisson process characterized with and exponential distribution of episilencing doses with mean dj . In addition to providing mathematical functions for evaluating the single-target-gene episilencing probability, functions are also provided for the multi-target-gene episilencing probability for simultaneously silencing of multiple tumor-suppressor-miRNA genes. Functional relationships are first developed for moderate doses where adaptive responses are unlikely and are then modified for low doses where adaptation can occur. Results apply to a specific follow-up time t after carcinogen exposure that exceeds the maximum time for the occurrence of an induced episilencing event.

Low-dose gamma-irradiation inhibits IL-6 secretion from human lung fibroblasts that promotes bronchial epithelial cell transformation by cigarette-smoke carcinogen.

Despite decades of research in defining the health effects of low-dose (<100 mGy) ionizing photon radiation (LDR), the relationship between LDR and human cancer risk remains elusive. Because chemical carcinogens modify the tumor microenvironment, which is critical for cancer development, we investigated the role and mechanism of LDR in modulating the response of stromal cells to chemical carcinogen-induced lung cancer development. Secretion of proinflammatory cytokines such as interleukin-6 (IL-6), CXCL1 and CXCL5 from human lung fibroblasts was induced by cigarette-smoke carcinogen benzo[a]pyrene diol epoxide (BPDE), which was inhibited by a single dose of LDR. The activation of NF-κB, which is important for BPDE-induced IL-6 secretion, was also effectively suppressed by LDR. In addition, conditioned media from BPDE-treated fibroblasts activated STAT3 in the immortalized normal human bronchial epithelial cell line Beas-2B, which was blocked with an IL-6 neutralizing antibody. Conditioned medium from LDR-primed and BPDE-treated fibroblast showed diminished capacity in activating STAT3. Furthermore, IL-6 enhanced BPDE-induced Beas-2B cell transformation in vitro. These results suggest that LDR inhibits cigarette smoke-induced lung carcinogenesis by suppressing secretion of cytokines such as IL-6 from fibroblasts in lung tumor-prone microenvironment.

Assessing potential radiological harm to fukushima recovery workers.

A radiological emergency exists at the Fukushima Daiichi (Fukushima I) nuclear power plant in Japan as a result of the March 11, 2011 magnitude 9.0 earthquake and the massive tsunami that arrived later. News media misinformation related to the emergency triggered enormous social fear worldwide of the radioactivity that is being released from damaged fuel rods. The heroic recovery workers are a major concern because they are being exposed to mostly gamma radiation during their work shifts and life-threatening damage to the radiosensitive bone marrow could occur over time. This paper presents a way in which the bone marrow equivalent dose (in millisieverts), as estimated per work shift, could be used along with the hazard function model previously developed for radiological risk assessment to repeatedly check for potential life-threatening harm (hematopoietic system damage) to workers. Three categories of radiation hazard indication are proposed: 1, life-threatening damage unlikely; 2, life-threatening damage possible; 3, life-threatening damage likely. Categories 2 and 3 would be avoided if the whole body effective dose did not exceed the annual effective dose limit of 250 mSv. For down-wind populations, hormetic effects (activated natural protective processes) are much more likely than are deleterious effects.