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.

Are Lockdowns Effective in Managing Pandemics?

The present coronavirus crisis caused a major worldwide disruption which has not been experienced for decades. The lockdown-based crisis management was implemented by nearly all the countries, and studies confirming lockdown effectiveness can be found alongside the studies questioning it. In this work, we performed a narrative review of the works studying the above effectiveness, as well as the historic experience of previous pandemics and risk-benefit analysis based on the connection of health and wealth. Our aim was to learn lessons and analyze ways to improve the management of similar events in the future. The comparative analysis of different countries showed that the assumption of lockdowns' effectiveness cannot be supported by evidence-neither regarding the present COVID-19 pandemic, nor regarding the 1918-1920 Spanish Flu and other less-severe pandemics in the past. The price tag of lockdowns in terms of public health is high: by using the known connection between health and wealth, we estimate that lockdowns may claim 20 times more life years than they save. It is suggested therefore that a thorough cost-benefit analysis should be performed before imposing any lockdown for either COVID-19 or any future pandemic.

Cost-Effectiveness Threshold for Healthcare: Justification and Quantification.

Every public health expenditure, including the one that saves lives or extends life expectancy of particular persons (target population), bears a cost. Although cost-effectiveness analysis (CEA) is routinely performed in health policy, ethical justification of CEA is rarely discussed. Also, there is neither consensus value nor even consensus method for determining cost-effectiveness threshold (CET) for life-extending measures. In this study, we performed ethical analysis of CEA by policy impact assessment based on connection of health and wealth (poorer people have statistically shorter life expectancies) and concluded that CEA is not only a practical but also an ethical necessity. To quantify CET, we used three independent methods: (1) literature survey of analyzing salaries in risky occupations, (2) utilizing Prospect Theory suggesting that people value their lives in monetary terms twice more than their lifetime earnings, and (3) literature survey of the U.S. current legal practice. To the best of our knowledge, nobody applied method (2) to determine CET. The three methods yielded rather similar results with CET about 1.0 ± 0.4 gross domestic product per capita (GDPpc) per quality-adjusted life-year. Therefore, a sum of not higher than 140% GDPpc is statistically sufficient to "purchase" an additional year of life-or, alternatively, to "rob" one year of life if taken away. Therefore, 140% GDP per capita per quality-adjusted life-year should be considered as the upper limit of prudent and ethically justified expenditure on life extension programs.

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.

Assessment of probable scenarios of radiological emergency and their consequences.

PURPOSE: Despite the vast amount of literature on radiological emergencies, to the best of our knowledge there is no systematic review of probable scenarios and their consequences. This work aimed for compiling such review. MATERIALS AND METHODS: The authors comprised a Red Team - that is, simulated best efforts to inflict maximal damage to the society by various means of radiological attacks. Nuclear warfare including improvised nuclear devices is beyond the scope of this work. RESULTS: The direct radiogenic health consequences of any conceivable radiological accident, natural or man-made, are much less dangerous than those which are usually perceived. In each scenario, direct health effects are only a small part of the damage caused by fear and over-reaction; the damage is somewhat independent of the small health effect predicted for most of the scenarios. The reason is that nuclear radiation has become perceptually connected with nuclear apocalypses. This connection has caused the emotional description of radiological emergencies to frequently substitute quantitative considerations. For example, Chernobyl and Fukushima became major humanitarian disasters not because of the radiation itself but because of the over-reaction of both the authorities and the public, that led to the unjustified relocation of hundreds of thousands of people. In Fukushima, the evacuation was not justified at all and in Chernobyl the evacuated zone should have been re-populated after 1 month. CONCLUSIONS: It is vital to educate decision makers, first responders and the public about the factual extent of possible radiological consequences, as well as about the very real danger of over-reaction. Since the extent of the countermeasures deployed is unavoidably connected, in the eye of the public, with the extent of the danger, we suggest launching educational campaigns that explain the factual extent of the radiation risk, followed by easing regulations and narrowing safety margins. Such measures will probably be the most efficient method of countering radiological terrorism: by depriving any adversary of the most important ability which is to cause an over-reaction.

Consequences of a large-scale nuclear accident and guidelines for evacuation: a cost-effectiveness analysis.

PURPOSE: We aimed for a quantitative evaluation that justifies guidelines for evacuation which take into consideration both the human and economic costs. To the best of our knowledge, such an evaluation has not been performed yet. The present guidelines published by the International Atomic Energy Agency (IAEA) are probably based on averting radiation risk only; IAEA did not cite any quantitative estimation of the human cost of evacuation. MATERIALS AND METHODS: Quantitative estimation of the human and monetary costs of evacuation and, alternatively, the human and monetary costs of radiation exposure (non-evacuation). Associating human life with monetary value is psychologically difficult and somewhat challenging ethically; however, there is no escape from such an association (cost-effectiveness analysis) when making decisions regarding public health and safety, since extraneous public expenditures lead to a statistical life shortening. Estimating worst-case health consequences of irradiation, we used the conservative linear no-threshold (LNT) model because this model is widely used in spite of its controversy. In our estimation of the human cost of evacuation, we considered three factors: (a) direct loss of life (after Fukushima, 1% of the evacuees died within 2 years due to causes directly related to their evacuation), (b) loss of quality of life, and (c) loss of wealth leading to loss of life. The connection of economic loss with loss of life was performed according to the median cost-effectiveness threshold of 50-100 thousand USD per quality-adjusted life year. RESULTS: Even according to mortality calculations based on LNT, the overall loss of life due to evacuation is higher than the loss of life due to irradiation if the population-averaged first-year radiation dose is 500 mSv or less. CONCLUSIONS: Based on the performed analysis, we suggest avoiding evacuation if the projected first-year dose is below 500 mSv. This suggested action level is about five-fold higher than the action level presently recommended by the IAEA (100 mSv per year).

Vaccinations: Mandatory or Voluntary? Risk-Benefit Analysis.

The discussion regarding mandatory vaccination of children centers mainly around the question of whether producing public good has precedence over the freedom of individuals. In the core of this discussion lies the assumption that mass immunization has been proven as a public good, based on the experts' opinion that there is no proof of significant damage caused by vaccinations. We suggest, however, that this argument is insufficient. Namely, beside acute effects, vaccination (as any intervention) can shorten long-term life expectancy. If, for example, vaccination is intended to prevent an illness that causes 0.05% mortality or permanent disability population-wide (like in the case of measles), the population-wide vaccination can be considered as a public good only if the vaccination itself does not cause life shortening by 0.05%, that is, by about 15 days. Absence of such a small long-term effect has not been proven and cannot be proven in principle for several decades to come. The lack of proof of damage is not proof of lack of damage; in any dispute, the burden of proof lies with those who lay charges. Therefore, we conclude that it is inappropriate today to enforce mandatory immunization.

Interests, Bias, and Consensus in Science and Regulation.

Scientists are human. As such, they are prone to bias based on political and economic interests. While conflicts of interest are usually associated with private funding, research funded by public sources is also subject to special interests and therefore prone to bias. Such bias may lead to consensus not based on evidence. While appealing to scientific consensus is a legitimate tool in public debate and regulatory decisions, such an appeal is illegitimate in scientific discussion itself. We provide examples of decades-long scientific consensus on erroneous hypotheses. For policy advice purposes, a scientific statement or model should be considered as the subject of proper scientific consensus only if shared by those who would directly benefit from proving it wrong. Otherwise, specialists from adjacent fields of science and technology should be consulted.

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.