If You Torture Your Data Long Enough, It Will Confess to Anything: On the Epidemiological Basis of the LNT Model.

This note deals with epidemiological data interpretation supporting the linear no-threshold model, as opposed to emerging evidence of adaptive response and hormesis from molecular biology in vitro and animal models. Particularly, the US-Japan Radiation Effects Research Foundation's lifespan study of atomic bomb survivors is scrutinized. We stress the years-long lag of the data processing after data gathering and evolving statistical models and methodologies across publications. The necessity of cautious interpretation of radiation epidemiology results is emphasized.

Artificial intelligence in biology and medicine, and radioprotection research: perspectives from Jerusalem.

While AI is widely used in biomedical research and medical practice, its use is constrained to few specific practical areas, e.g., radiomics. Participants of the workshop on "Artificial Intelligence in Biology and Medicine" (Jerusalem, Feb 14-15, 2023), both researchers and practitioners, aimed to build a holistic picture by exploring AI advancements, challenges and perspectives, as well as to suggest new fields for AI applications. Presentations showcased the potential of large language models (LLMs) in generating molecular structures, predicting protein-ligand interactions, and promoting democratization of AI development. Ethical concerns in medical decision making were also addressed. In biological applications, AI integration of multi-omics and clinical data elucidated the health relevant effects of low doses of ionizing radiation. Bayesian latent modeling identified statistical associations between unobserved variables. Medical applications highlighted liquid biopsy methods for non-invasive diagnostics, routine laboratory tests to identify overlooked illnesses, and AI's role in oral and maxillofacial imaging. Explainable AI and diverse image processing tools improved diagnostics, while text classification detected anorexic behavior in blog posts. The workshop fostered knowledge sharing, discussions, and emphasized the need for further AI development in radioprotection research in support of emerging public health issues. The organizers plan to continue the initiative as an annual event, promoting collaboration and addressing issues and perspectives in AI applications with a focus on low-dose radioprotection research. Researchers involved in radioprotection research and experts in relevant public policy domains are invited to explore the utility of AI in low-dose radiation research at the next workshop.

The Theoretical Value of Whole-Lung Irradiation for COVID-19 Pneumonia: A Reasonable and Safe Solution until Targeted Treatments are Developed.

In this work, we considered the theoretical role of low-dose radiation therapy (approximately 0.5-1.0 Gy) in the treatment of respiratory distress syndrome associated with COVID-19 infection. Monte Carlo calculations were performed to gauge the ability to deliver low-dose radiation to the thoracic mid-plane using an orthovoltage machine. In addition, the potential harm of a single dose of 0.75 Gy (whole-lung irradiation) was assessed based on the recommendations of the BEIR-VII committee of the U.S. National Research Council. Based on the results of this work, it was determined that an orthovoltage machine (minimum 300 kVp) can be used to deliver 0.75 Gy dose to the lungs while respecting cutaneous tolerance. Using data from the BEIR-VII Committee, it is evident that the apparent benefits of such radiation treatment for patients suffering from severe manifestations of the COVID-19 infectious syndrome outweigh the potential loss of life due to radiation-induced malignancy. Although the vaccination against COVID-19 has become a reality, the spread and mortality in severely ill patients remain unacceptably high. The risk of outbreaks in the future is unknown. We suggest herein that low-dose radiotherapy at the bedside should be rigorously considered as a therapeutic option since it appears to be feasible and safe in the short and long term.

Low-dose ionizing radiation as a hormetin: experimental observations and therapeutic perspective for age-related disorders.

Hormesis is any kind of biphasic dose-response when low doses of some agents are beneficial while higher doses are detrimental. Radiation hormesis is the most thoroughly investigated among all hormesis-like phenomena, in particular in biogerontology. In this review, we aimed to summarize research evidence supporting hormesis through exposure to low-dose ionizing radiation (LDIR). Radiation-induced longevity hormesis has been repeatedly reported in invertebrate models such as C. elegans, Drosophila and flour beetles and in vertebrate models including guinea pigs, mice and rabbits. On the contrary, suppressing natural background radiation was repeatedly found to cause detrimental effects in protozoa, bacteria and flies. We also discussed here the possibility of clinical use of LDIR, predominantly for age-related disorders, e.g., Alzheimer's disease, for which no remedies are available. There is accumulating evidence that LDIR, such as those commonly used in X-ray imaging including computer tomography, might act as a hormetin. Of course, caution should be exercised when introducing new medical practices, and LDIR therapy is no exception. However, due to the low average residual life expectancy in old patients, the short-term benefits of such interventions (e.g., potential therapeutic effect against dementia) may outweigh their hypothetical delayed risks (e.g., cancer). We argue here that assessment and clinical trials of LDIR treatments should be given priority bearing in mind the enormous economic, social and ethical implications of potentially-treatable, age-related disorders.

Ethics of Adoption and Use of the Linear No-Threshold Model.

The linear no-threshold (LNT) model of ionizing radiation-induced cancer assumes that every increment of radiation dose, no matter how small, constitutes an increased cancer risk for humans. Linear no-threshold is presently the most widely applied model for radiation risk assessment. As such, it imposes very heavy burden on the society in both economic and human terms. This model, which was adopted in late 1950s in the wake of massive government investments in science, is controversial and raises important ethical issues. This article identifies 2 issues often missed: scientists usurping the role of policy makers and seeking funding and power. These issues should be considered together with the scientific controversy raging over the validity of the LNT model and the multiple other ethical issues regarding its ongoing use.

Health Impacts of Low-Dose Ionizing Radiation: Current Scientific Debates and Regulatory Issues.

Health impacts of low-dose ionizing radiation are significant in important fields such as X-ray imaging, radiation therapy, nuclear power, and others. However, all existing and potential applications are currently challenged by public concerns and regulatory restrictions. We aimed to assess the validity of the linear no-threshold (LNT) model of radiation damage, which is the basis of current regulation, and to assess the justification for this regulation. We have conducted an extensive search in PubMed. Special attention has been given to papers cited in comprehensive reviews of the United States (2006) and French (2005) Academies of Sciences and in the United Nations Scientific Committee on Atomic Radiation 2016 report. Epidemiological data provide essentially no evidence for detrimental health effects below 100 mSv, and several studies suggest beneficial (hormetic) effects. Equally significant, many studies with in vitro and in animal models demonstrate that several mechanisms initiated by low-dose radiation have beneficial effects. Overall, although probably not yet proven to be untrue, LNT has certainly not been proven to be true. At this point, taking into account the high price tag (in both economic and human terms) borne by the LNT-inspired regulation, there is little doubt that the present regulatory burden should be reduced.

Evidence of a Dose-Rate Threshold for Life Span Reduction of Dogs Exposed Lifelong to γ-Radiation.

Our return to a study on dogs exposed lifelong to cobalt-60 γ-radiation was prompted by a comment that data in dog studies have large statistical errors due to the small number of dogs. We located an earlier article on the same study that had a better mortality curve for the dogs in each dose-rate group. The median life span of the dogs in each group was tabulated, and the standard error of each was calculated. No statistically significant shortening of median life span was observed for the lowest dose-rate group at any reasonable significance level (P value: .005-.05), whereas for dogs with higher irradiation rates, life span shortening was statistically significant at highest reasonable significance level (P value: .005). The results were entered on a graph of life span versus dose rate, assuming a threshold dose-response model. The fitted line indicates that the dose-rate threshold for γ-radiation induced life span reduction is about 600 mGy per year, which is close to the value we found previously. Making allowance for the calculated standard errors, we conclude that this threshold is in the range from 300 to 1100 mGy per year. This evidence is relevant for emergency measures actions (evacuation of residents) and for nuclear waste management.

Evidence That Lifelong Low Dose Rates of Ionizing Radiation Increase Lifespan in Long- and Short-Lived Dogs.

After the 1956 radiation scare to stop weapons testing, studies focused on cancer induction by low-level radiation. Concern has shifted to protecting "radiation-sensitive individuals." Since longevity is a measure of health impact, this analysis reexamined data to compare the effect of dose rate on the lifespans of short-lived (5% and 10% mortality) dogs and on the lifespans of dogs at 50% mortality. The data came from 2 large-scale studies. One exposed 10 groups to different γ dose rates; the other exposed 8 groups to different lung burdens of plutonium. Reexamination indicated that normalized lifespans increased more for short-lived dogs than for average dogs, when radiation was moderately above background. This was apparent by interpolating between the lifespans of nonirradiated dogs and exposed dogs. The optimum lifespan increase appeared at 50 mGy/y. The threshold for harm (decreased lifespan) was 700 mGy/y for 50% mortality dogs and 1100 mGy/y for short-lived dogs. For inhaled α-emitting particulates, longevity was remarkably increased for short-lived dogs below the threshold for harm. Short-lived dogs seem more radiosensitive than average dogs and they benefit more from low radiation. If dogs model humans, this evidence would support a change to radiation protection policy. Maintaining exposures "as low as reasonably achievable" (ALARA) appears questionable.

Modeling of Irradiated Cell Transformation: Dose- and Time-Dependent Effects.

We report here on various biophysical aspects of irradiated cells, beginning with a phenomenological description of radiation-induced cancer cells. This description includes detrimental factors such as chromosomal aberrations, as well as beneficial factors, such as adaptive response. Also discussed here is the dose- and time-dependent evolution of cancer cells using a purely mathematical approach. The general dose-response shape, which is sigmoidal, is shown to be modified by such mechanisms as adaptive response or bystander effect. The many aspects of the sigmoid function, which most appropriately demonstrates the relationships among irradiated organisms, are discussed here as well. Finally, the balance equation is presented as the most general relationship for irradiated cell behavior.

Changing Attitude Toward Radiation Carcinogenesis and Prospects for Novel Low-Dose Radiation Treatments.

All procedures involving ionizing radiation, whether diagnostic or therapeutic, are subject to strict regulation, and public concerns have been raised about even the low levels of radiation exposures involved in diagnostic imaging. During the last 2 decades, there are signs of more balanced attitude to ionizing radiation hazards, as opposed to the historical "radiophobia." The linear no-threshold hypothesis, based on the assumption that every radiation dose increment constitutes increased cancer risk for humans, is increasingly debated. In particular, the recent memorandum of the International Commission on Radiological Protection admits that the linear no-threshold hypothesis predictions at low doses (that International Commission on Radiological Protection itself has used and continues to use) are "speculative, unproven, undetectable, and 'phantom'." Moreover, numerous experimental, ecological, and epidemiological studies suggest that low doses of ionizing radiation may actually be beneficial to human health. Although these advances in scientific understanding have not yet yielded significant changes in radiation regulation and policy, we are hopeful such changes may happen in the relatively near future. This article reviews the present status of the low-dose radiation hazard debate and outlines potential opportunities in the field of low-dose radiation therapy.

Regarding the Credibility of Data Showing an Alleged Association of Cancer with Radiation from CT Scans.

Computed tomography (CT) scans are of high clinical value as a diagnostic technique, and new applications continue to be identified. However, their application is challenged by emerging concerns regarding carcinogenesis from their radiation. Recent articles made a significant contribution to the above-mentioned concerns by reporting evidence for direct association of the radiation from CT scans with cancer. Such interpretation of the data has already been criticized; there is the possibility of reverse causation due to confounding factors. Nevertheless, such work has had a high impact, with one article being cited more than 300 times from the Web of Science Core Collection within 2 years. However, the data points on cancer relative risk versus CT dose in that article fit straight lines corresponding to the linear no-threshold hypothesis suspiciously well. Here, by applying rigorous statistical analysis, it is shown that the probability of the fit truly being that good or better is only 2%. The results of such studies therefore appear "too good to be true" and the credibility of their conclusions must be questioned.

Atomic Bomb Survivors Life-Span Study: Insufficient Statistical Power to Select Radiation Carcinogenesis Model.

The atomic bomb survivors life-span study (LSS) is often claimed to support the linear no-threshold hypothesis (LNTH) of radiation carcinogenesis. This paper shows that this claim is baseless. The LSS data are equally or better described by an s-shaped dependence on radiation exposure with a threshold of about 0.3 Sievert (Sv) and saturation level at about 1.5 Sv. A Monte-Carlo simulation of possible LSS outcomes demonstrates that, given the weak statistical power, LSS cannot provide support for LNTH. Even if the LNTH is used at low dose and dose rates, its estimation of excess cancer mortality should be communicated as 2.5% per Sv, i.e., an increase of cancer mortality from about 20% spontaneous mortality to about 22.5% per Sv, which is about half of the usually cited value. The impact of the "neutron discrepancy problem" - the apparent difference between the calculated and measured values of neutron flux in Hiroshima - was studied and found to be marginal. Major revision of the radiation risk assessment paradigm is required.

Reconsidering Health Consequences of the Chernobyl Accident.

The Chernobyl accident led to major human suffering caused by the evacuation and other counter-measures. However, the direct health consequences of the accident-related radiation exposures, besides the acute effects and small number of thyroid cancers, have not been observed. This absence is challenged by some influential groups affecting public policies who claim that the true extent of radiogenic health consequences is covered up. We consider such claims. The most conservative (in this case - overestimating) linear no-threshold hypothesis was used to calculate excess cancer expectations for cleanup workers, the population of the contaminated areas and the global population. Statistical estimations were performed to verify whether such expected excess was detectable. The calculated cancer excess for each group is much less than uncertainties in number of cancer cases in epidemiological studies. Therefore the absence of detected radiation carcinogenesis is in full correspondence with the most conservative a priori expectations. Regarding the cover-up claims, rational choice analysis was performed. Such analysis shows that these claims are ill-founded. The present overcautious attitude to radiological hazards should be corrected in order to mitigate the present suffering and to avoid such suffering in the future.

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.