Linear No-Threshold Model VS. Radiation Hormesis

The atomic bomb survivor cancer mortality data have been used in the past to justify the use of the linear no-threshold (LNT) model for estimating the carcinogenic effects of low dose radiation. An analysis of the recently updated atomic bomb survivor cancer mortality dose-response data shows that the data no longer support the LNT model but are consistent with a radiation hormesis model when a correction is applied for a likely bias in the baseline cancer mortality rate. If the validity of the phenomenon of radiation hormesis is confirmed in prospective human pilot studies, and is applied to the wider population, it could result in a considerable reduction in cancers. The idea of using radiation hormesis to prevent cancers was proposed more than three decades ago, but was never investigated in humans to determine its validity because of the dominance of the LNT model and the consequent carcinogenic concerns regarding low dose radiation. Since cancer continues to be a major health problem and the age-adjusted cancer mortality rates have declined by only ∼10% in the past 45 years, it may be prudent to investigate radiation hormesis as an alternative approach to reduce cancers. Prompt action is urged.     

Metabolic efficiency in response to environmental agents predicts hormesis and invalidates the linear no-threshold premise: ionizing radiation as a case study

Hormesis derives from high metabolic efficiency and hence high fitness that evolve in response to single and multiple environmental agents in low to moderate stress habitats. Consequently, nonlinear fitness continua are an evolutionary expectation for all environmental agents, which invalidates the LNT premise. For ionizing radiation, hormesis is interpreted to be adaptation to background radiation exposures, combined with adaptation to higher radiation exposures dependent on metabolic protection from the array of other abiotic stresses in the environment. This model of radiation hormesis renders suggestions of therapeutic radiation supplementation redundant because of similar health effects from other environmental agents. Furthermore, the model is compatible with a return of exposure levels for radiation protection to higher doses than are presently permissible, a deduction with substantial economic benefits.     

Metabolic Efficiency in Response to Environmental Agents Predicts Hormesis and Invalidates the Linear No-Threshold Premise: Ionizing Radiation as a Case Study

Hormesis derives from high metabolic efficiency and hence high fitness that evolve in response to single and multiple environmental agents in low to moderate stress habitats. Consequently, nonlinear fitness continua are an evolutionary expectation for all environmental agents, which invalidates the LNT premise. For ionizing radiation, hormesis is interpreted to be adaptation to background radiation exposures, combined with adaptation to higher radiation exposures dependent on metabolic protection from the array of other abiotic stresses in the environment. This model of radiation hormesis renders suggestions of therapeutic radiation supplementation redundant because of similar health effects from other environmental agents. Furthermore, the model is compatible with a return of exposure levels for radiation protection to higher doses than are presently permissible, a deduction with substantial economic benefits.     

Atomic Bomb Health Benefits

Media reports of deaths and devastation produced by atomic bombs convinced people around the world that all ionizing radiation is harmful. This concentrated attention on fear of miniscule doses of radiation. Soon the linear no threshold (LNT) paradigm was converted into laws. Scientifically valid information about the health benefits from low dose irradiation was ignored. Here are studies which show increased health in Japanese survivors of atomic bombs. Parameters include decreased mutation, leukemia and solid tissue cancer mortality rates, and increased average lifespan. Each study exhibits a threshold that repudiates the LNT dogma. The average threshold for acute exposures to atomic bombs is about 100 cSv. Conclusions from these studies of atomic bomb survivors are:

• One burst of low dose irradiation elicits a lifetime of improved health.
• Improved health from low dose irradiation negates the LNT paradigm.
• Effective triage should include radiation hormesis for survivor treatment.

     

Evidence Supporting Radiation Hormesis in Atomic Bomb Survivor Cancer Mortality Data

A recent update on the atomic bomb survivor cancer mortality data has concluded that excess relative risk (ERR) for solid cancers increases linearly with dose and that zero dose is the best estimate for the threshold, apparently validating the present use of the linear no threshold (LNT) model for estimating the cancer risk from low dose radiation. A major flaw in the standard ERR formalism for estimating cancer risk from radiation (and other carcinogens) is that it ignores the potential for a large systematic bias in the measured baseline cancer mortality rate, which can have a major effect on the ERR values. Cancer rates are highly variable from year to year and between adjacent regions and so the likelihood of such a bias is high. Calculations show that a correction for such a bias can lower the ERRs in the atomic bomb survivor data to negative values for intermediate doses. This is consistent with the phenomenon of radiation hormesis, providing a rational explanation for the decreased risk of cancer observed at intermediate doses for which there is no explanation based on the LNT model. The recent atomic bomb survivor data provides additional evidence for radiation hormesis in humans.     

Model Uncertainty via the Integration of Hormesis and LNT as the Default in Cancer Risk Assessment

On June 23, 2015, the US Nuclear Regulatory Commission (NRC) issued a formal notice in the Federal Register that it would consider whether “it should amend its ‘Standards for Protection Against Radiation’ regulations from the linear non-threshold (LNT) model of radiation protection to the hormesis model.” The present commentary supports this recommendation based on the (1) flawed and deceptive history of the adoption of LNT by the US National Academy of Sciences (NAS) in 1956; (2) the documented capacity of hormesis to make more accurate predictions of biological responses for diverse biological end points in the low-dose zone; (3) the occurrence of extensive hormetic data from the peer-reviewed biomedical literature that revealed hormetic responses are highly generalizable, being independent of biological model, end point measured, inducing agent, level of biological organization, and mechanism; and (4) the integration of hormesis and LNT models via a model uncertainty methodology that optimizes public health responses at 10⁻⁴. Thus, both LNT and hormesis can be integratively used for risk assessment purposes, and this integration defines the so-called “regulatory sweet spot.”     

Hormesis: an adaptive expectation with emphasis on ionizing radiation

Non-linear fitness gradients with maxima between extremes are expected for any environmental variable to which free-living populations are exposed. For exceedingly toxic agents, including ionizing radiation, such deviations from linearity are close to zero exposure and are conventionally called hormesis. Accordingly, hormesis is an extreme version of the non-linear fitness gradients for general environmental stresses such as temperature fluctuations, for which maximum fitness occurs at the moderate temperature fluctuations to which free-living populations are most commonly exposed. Some metabolic reserves should occur under moderate temperature stresses because of the need for pre-adaptation enabling survival during exposure to occasional periods of more extreme stress, especially at species borders where selection for stress resistance is likely to be most intense. Because heat shock proteins are induced by all stresses, adaptation to extreme temperatures should translate into adaptation to other stresses. Consequently, metabolic reserves from adaptation to extreme temperatures in the past should translate into protection from correlated abiotic stresses, especially in human populations where modern cultural processes are now ameliorating exposure to extreme stresses. Ambient and man-made radiations of non-catastrophic dimensions should therefore lead to stress-derived radiation hormesis. Other stresses can, in principle, be incorporated into this model. Accordingly, evolutionary and ecological considerations suggest two components of hormesis in relation to ionizing radiation: background radiation hormesis based upon the background exposure to which all organisms on earth are subjected; and stress-derived radiation hormesis. Exposure under stress-derived radiation hormesis is considerably larger than under background radiation hormesis, so significant deleterious effects from non-catastrophic radiation normally may be impossible to detect. Suggestions are provided for testing such postulated deviations from the commonly assumed linear no-threshold (LNT) hypothesis for the biological consequences of exposure to radiation.     

Selenosugar and trimethylselenonium among urinary Se metabolites: dose- and age-related changes

This paper assesses historical reasons that may account for the marginalization of hormesis as a dose-response model in the biomedical sciences in general and toxicology in particular. The most significant and enduring explanatory factors are the early and close association of the concept of hormesis with the highly controversial medical practice of homeopathy and the difficulty in assessing hormesis with high-dose testing protocols which have dominated the discipline of toxicology, especially regulatory toxicology. The long-standing and intensely acrimonious conflict between homeopathy and "traditional" medicine (allopathy) lead to the exclusion of the hormesis concept from a vast array of medical- and public health-related activities including research, teaching, grant funding, publishing, professional societal meetings, and regulatory initiatives of governmental agencies and their advisory bodies. Recent publications indicate that the hormetic dose-response is far more common and fundamental than the dose-response models [threshold/linear no threshold (LNT)] used in toxicology and risk assessment, and by governmental regulatory agencies in the establishment of exposure standards for workers and the general public. Acceptance of the possibility of hormesis has the potential to profoundly affect the practice of toxicology and risk assessment, especially with respect to carcinogen assessment.     

Effects of cobalt-60 exposure on health of Taiwan residents suggest new approach needed in radiation protection

The conventional approach for radiation protection is based on the ICRP's linear, no threshold (LNT) model of radiation carcinogenesis, which implies that ionizing radiation is always harmful, no matter how small the dose. But a different approach can be derived from the observed health effects of the serendipitous contamination of 1700 apartments in Taiwan with cobalt-60 (T(1/2) = 5.3 y). This experience indicates that chronic exposure of the whole body to low-dose-rate radiation, even accumulated to a high annual dose, may be beneficial to human health. Approximately 10,000 people occupied these buildings and received an average radiation dose of 0.4 Sv, unknowingly, during a 9-20 year period. They did not suffer a higher incidence of cancer mortality, as the LNT theory would predict. On the contrary, the incidence of cancer deaths in this population was greatly reduced-to about 3 per cent of the incidence of spontaneous cancer death in the general Taiwan public. In addition, the incidence of congenital malformations was also reduced--to about 7 per cent of the incidence in the general public. These observations appear to be compatible with the radiation hormesis model. Information about this Taiwan experience should be communicated to the public worldwide to help allay its fear of radiation and create a positive impression about important radiation applications. Expenditures of many billions of dollars in nuclear reactor operation could be saved and expansion of nuclear electricity generation could be facilitated. In addition, this knowledge would encourage further investigation and implementation of very important applications of total-body, low-dose irradiation to treat and cure many illnesses, including cancer. The findings of this study are such a departure from expectations, based on ICRP criteria, that we believe that they ought to be carefully reviewed by other, independent organizations and that population data not available to the authors be provided, so that a fully qualified epidemiologically-valid analysis can be made. Many of the confounding factors that limit other studies used to date, such as the A-bomb survivors, the Mayak workers and the Chernobyl evacuees, are not present in this population exposure. It should be one of the most important events on which to base radiation protection standards.     

Radiation hormesis: the demise of a legitimate hypothesis

This paper examines the underlying factors that contributed to the marginalization of radiation hormesis in the early and middle decades of the 20th century. The most critical factor affecting the demise of radiation hormesis was a lack of agreement over how to define the concept of hormesis and quantitatively describe its dose-response features. If radiation hormesis had been defined as a modest overcompensation to a disruption in homeostasis as would have been consistent with the prevailing notion in the area of chemical hormesis, this would have provided the theoretical and practical means to blunt subsequent legitimate criticism of this hypothesis. A second critical factor undermining the radiation hormesis hypothesis was the generally total lack of recognition by radiation scientists of the concept of chemical hormesis which was markedly more advanced, substantiated and generalized than in the radiation domain. The third factor was that major scientific criticism of low dose stimulatory responses was galvanized at the time that the National Research Council (NRC) was organizing a national research agenda on radiation and the hormetic hypothesis was generally excluded from the future planned research opportunities. Furthermore, the criticisms of the leading scientists of the 1930s which undermined the concept of radiation hormesis were limited in scope and highly flawed and then perpetuated over the decades by other 'prestigious' experts who appeared to simply accept the earlier reports. This setting was then linked to a growing fear of radiation as a cause of birth defects, mutation and cancer, factors all reinforced by later concerns over the atomic bomb. Strongly supportive findings on hormetic effects in the 1940s by Soviet scientists were either generally not available to US scientists or disregarded as part of the Cold War mindset without adequate analysis. Finally, a massive, but poorly designed, US Department of Agriculture experiment in the late 1940s to assess the capacity for low dose plant stimulation by radionuclides failed to support the hormetic hypothesis thereby markedly lessening enthusiasm for research and funding in this area. Thus, the combination of a failed understanding of the hormetic hypothesis and its linkage with a strong chemical hormesis database, flawed analyses by prestigious scientists at the critical stage of scientific research development, reinforced by a Cold War mentality led to marginalization of an hypothesis (i.e., radiation hormesis) that had substantial scientific foundations and generalizability.     

Hormesis and radiation safety norms

Today's radiation safety norms are based on the linear no-threshold theory (LNT): extrapolation of the dose-response relationships down to the minimal doses, where such relationships are unproven and can be inverse due to hormesis. The most promising way to obtaining reliable data on the dose-effect relationships for low radiation doses would be large-scale animal experiments. Outstanding published data on carcinogenic effects of the doses e.g. below 100 mSv should be verified by experiments. Arguments against applicability of the LNT to the doses comparable to those from the natural radiation background are discussed. Furthermore it is stressed that medical consequences of the Chernobyl accident have been overestimated; and this theme has been exploited to strangle development of atomic energy and to elevate prices for fossil fuels. Worldwide introduction of nuclear energy will be possible only after a concentration of authority within a powerful international executive. It would enable the construction of nuclear reactors in optimally suitable places, considering all sociopolitical, geographical, and geological conditions, which would contribute to the prevention of accidents like in Japan in 2011. A concluding point is that radiation safety norms are exceedingly restrictive and should be revised to become more realistic and workable. Elevation of the limits must be accompanied by measures guaranteeing their strict observance. It is also concluded that there are no evidence-based contraindications to fivefold elevation of the total equivalent effective doses to individual members of the public (up to 5 mSv/year), and doubling of the limits for professional exposures.     

Linear No-Threshold model and standards for protection against radiation

In response to the three petitions by Carol S. Marcus, Mark L. Miller, and Mohan Doss, dated February 9, February 13, and February 24, 2015, respectively, the Nuclear Regulatory Commission (NRC or the Commission) has announced that it is considering assessing its choice of dose–response model, the Linear No-Threshold (LNT) model, for exposure to ionizing radiation. This comment is designed to assist the Commission in evaluating the merits of a review of the default dose–response model it uses as the basis for the Standards for Protection against Radiation regulations. It extends the petitioners' argument in favor of reexamining the default hypothesis (LNT) and taking consideration of low-dose hormesis for two main reasons: 1) Failure to review the LNT hypothesis may jeopardize the NRC's mission to protect public health and safety; and 2) The National Research Council's guidelines for choosing adequate defaults indicate that the choice of low-dose default model is due for a reevaluation.     

Hypothesis testing and the choice of the dose-response model

The shape of the dose-response curve for exposure to ionising radiation is probably one of the most contentious issues in toxicology. The initial assumption was that there was a threshold to the appearance of a health detriment, including cancer, with the so-called linear-no-threshold (LNT) hypothesis first being introduced in the early 1960s. Since that time a number of models have been suggested, and present work in health physics, toxicology and epidemiology is concerned with questions about both the shape of the dose-response curve and whether or not a threshold exists. This paper presents an analysis of the robustness of the LNT hypothesis from a philosophy of science standpoint-arguing that claims about dose-response curve need to pay more attention to the assumptions and auxillary hypotheses behind choices, and that further mechanistic studies are required to unravel the effects of exposure to ionising radiation. It suggests that whereas LNT falls short of the requirements for a good scientific hypothesis, it is a reasonable model for regulating the carcinogenic and hereditary effects of radiation exposure.     

Origin of the linearity no threshold (LNT) dose–response concept

This paper identifies the origin of the linearity at low-dose concept [i.e., linear no threshold (LNT)] for ionizing radiation-induced mutation. After the discovery of X-ray-induced mutations, Olson and Lewis (Nature 121(3052):673–674, 1928) proposed that cosmic/terrestrial radiation-induced mutations provide the principal mechanism for the induction of heritable traits, providing the driving force for evolution. For this concept to be general, a LNT dose relationship was assumed, with genetic damage proportional to the energy absorbed. Subsequent studies suggested a linear dose response for ionizing radiation-induced mutations (Hanson and Heys in Am Nat 63(686):201–213, 1929; Oliver in Science 71:44–46, 1930), supporting the evolutionary hypothesis. Based on an evaluation of spontaneous and ionizing radiation-induced mutation with Drosophila, Muller argued that background radiation had a negligible impact on spontaneous mutation, discrediting the ionizing radiation-based evolutionary hypothesis. Nonetheless, an expanded set of mutation dose–response observations provided a basis for collaboration between theoretical physicists (Max Delbruck and Gunter Zimmer) and the radiation geneticist Nicolai Timoféeff-Ressovsky. They developed interrelated physical science-based genetics perspectives including a biophysical model of the gene, a radiation-induced gene mutation target theory and the single-hit hypothesis of radiation-induced mutation, which, when integrated, provided the theoretical mechanism and mathematical basis for the LNT model. The LNT concept became accepted by radiation geneticists and recommended by national/international advisory committees for risk assessment of ionizing radiation-induced mutational damage/cancer from the mid-1950s to the present. The LNT concept was later generalized to chemical carcinogen risk assessment and used by public health and regulatory agencies worldwide.     

Perspective on the Use of LNT for Radiation Protection and Risk Assessment By The U.S. Environmental Protection Agency

The U.S. Environmental Protection Agency (EPA) bases its risk assessments, regulatory limits, and nonregulatory guidelines for population exposures to low level ionizing radiation on the linear no-threshold (LNT) hypothesis, which assumes that the risk of cancer due to a low dose exposure is proportional to dose, with no threshold. The use of LNT for radiation protection purposes has been repeatedly endorsed by authoritative scientific advisory bodies, including the National Academy of Sciences’ BEIR Committees, whose recommendations form a primary basis of EPA’s risk assessment methodology. Although recent radiobiological findings indicate novel damage and repair processes at low doses, LNT is supported by data from both epidemiology and radiobiology. Given the current state of the science, the consensus positions of key scientific and governmental bodies, as well as the conservatism and calculational convenience of the LNT assumption, it is unlikely that EPA will modify this approach in the near future.     

Commentary on Inhaled 239PUO2 in Dogs — A Prophylaxis Against Lung Cancer?

Several studies on the effect of inhaled plutonium-dioxide particulates and the incidence of lung tumors in dogs reveal beneficial effects when the cumulative alpha-radiation dose is low. There is a threshold at an exposure level of about 100 cGy for excess tumor incidence and reduced lifespan. The observations conform to the expectations of the radiation hormesis dose-response model and contradict the predictions of the LNT hypothesis. These studies suggest investigating the possibility of employing low-dose alpha-radiation, such as from ²³⁹PuO₂ inhalation, as a prophylaxis against lung cancer.     

Hormesis [biological effects of low level exposures (BELLE)] and dermatology

Hormesis, or biological effects of low level exposures (BELLE), is characterized by nonmonotonic dose response which is biphasic, displaying opposite effects at low and high dose. Its occurrence has been documented across a broad range of biological models and diverse type of exposure. Since hormesis appears to be a relatively common phenomenon in many areas, the objective of this review is to explore its occurrence related to dermatology and its public health and risk assessment implication. Hormesis appears to be a common phenomenon in in-vitro skin biology. However, in vivo data are lacking and the clinical relevance of hormesis has yet to be determined. Better understanding of this phenomenon will likely lead to different strategies for risk assessment process employed in the fields of dermatologic toxicology and pharmacology. We believe that hormesis is a common phenomenon and should be given detailed consideration to its concept and its risk assessment implications, and how these may be incorporated into the experimental and regulatory processes in dermatology. The skin, with its unique characteristics, its accessibility, and the availability of non-invasive bioengineering and DNA microarray technology, will be a good candidate to extend the biology of hormesis.     

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.     

Radiation Hormesis: Historical Perspective and Implications for Low-Dose Cancer Risk Assessment

Current guidelines for limiting exposure of humans to ionizing radiation are based on the linear-no-threshold (LNT) hypothesis for radiation carcinogenesis under which cancer risk increases linearly as the radiation dose increases. With the LNT model even a very small dose could cause cancer and the model is used in establishing guidelines for limiting radiation exposure of humans. A slope change at low doses and dose rates is implemented using an empirical dose and dose rate effectiveness factor (DDREF). This imposes usually unacknowledged nonlinearity but not a threshold in the dose-response curve for cancer induction. In contrast, with the hormetic model, low doses of radiation reduce the cancer incidence while it is elevated after high doses. Based on a review of epidemiological and other data for exposure to low radiation doses and dose rates, it was found that the LNT model fails badly. Cancer risk after ordinarily encountered radiation exposure (medical X-rays, natural background radiation, etc.) is much lower than projections based on the LNT model and is often less than the risk for spontaneous cancer (a hormetic response). Understanding the mechanistic basis for hormetic responses will provide new insights about both risks and benefits from low-dose radiation exposure.     

Scientific Foundations of Hormesis. Part 2. Maturation,Strengths, Limitations,and Possible Applications in Toxicology,Pharmacology, and Epidemiology

The notion of hormesis has undergone numerous modifications in the course of the 20th century. Because of its unfortunate association with homeopathy, hormesis did not gain acceptance among biomedical professionals. The lack of a plausible mechanism for its occurrence may have contributed much to the rejection of this concept. This treatise outlines the conceptual struggle for an understanding of the widespread occurrence of low dose effects that appear to be opposite to those caused by high doses as also seen in hormesis. An incomplete conceptualization of time as a fundamental variable of effects (in addition to dose) is identified as one of the major reasons why hormetic responses were not observed more frequently than was reported by Calabrese and Baldwin.⁷ The definition of hormesis as an (over)compensation response to an inhibitory signal lacks a designation for (over)compensation responses to stimulatory signals in the other direction. Hormoligosis, which was coined by Luckey for all low-dose stimulatory responses of toxins, is suggested as a suitable term for generalizing the latter types of effects. Both types of effects are recognized as originating in a homeostatic overcompensation response that optimizes the ability of an organism to meet challenges beyond the limits of normal (unexercised) adaptation. Thus, repeated biochemical/physiologic/immunological, etc. exercises like physical exercise make an organism more fit and hence both hormetic and hormoligotic effects will have life-prolonging consequences. A more complete generalization was developed by linking hormesis/hormoligosis with the vast literature on Selye's general adaptation syndrome to stress. According to this broader view, stress is just one type of homeostatic exercise making organisms more fit for future biochemical/physiological/immunological, etc. challenges. Therefore, both hormesis and hormoligosis are manifestations of two nonmutational evolutionary principles — homeostasis and optimization.