Muller's genetic load/species extinction hypothesis.

The genetic load hypothesis of Hermann Muller raised the profound question of possible species extinction, even for humans, following a prolonged accumulation of recessive genes due to ionizing radiation exposure within the population. Two major mouse radiation research teams in the United States provided the most extensive tests of Muller's hypothesis. One group continued its study for more than two decades, over 82 consecutive generations, approximating 2500 human years. Even though Muller had stressed for decades his fear of species-threatening effects, no significant effects were observed for related factors such as reproductive fitness and longevity. Yet, the paper presenting the data of the 82-generation negative study has only been cited five times in 45 years. Altogether numerous laboratories worldwide collected vast amounts of data on mice, rats, and swine in an unsuccessful attempt to see if there was convincing evidence to support the genetic load theory and claims that species might deteriorate or be rendered extinct. This paper re-examines Muller's genetic load hypothesis with a new evaluation of how that hypothesis was tested and the significance of the findings, with most of those studies being completed before the BEIR I Committee Report in 1972. That committee briefly discussed the available evidence, mostly ignoring those results as they proceeded to make hereditary risk estimates both for (1) the first generation after a radiation exposure and (2) for the time, in the distant future, when a hypothetical genetic equilibrium would be reached. Their estimates assumed accumulation of harmful mutations and a linear no-threshold dose response extending all of the way down to a single ionization. More recent data on induction by ionizing radiation of dominant mutations that affect the skeletons of mice provide further robust supporting evidence that the generationally cumulative and LNT-based assumptions underpinning Muller's genetic load hypothesis are not correct.

Newly discovered letter: why Muller failed to cite the negative mouse mutation findings of Snell, preserving his chances to receive the Nobel Prize.

A recently acquired letter between Hermann Muller and his wife (March 21, 1933) reveals that Muller had learned that he had been nominated for the Nobel Prize in 1932 with about 1/3 of the total votes being supportive. Muller was hopeful that over time sufficient votes would lead to receiving the award. The knowledge of Muller on this matter and its timing provide a likely explanation why Muller never cited the negative mouse mutation findings of George Snell, performed under Muller's direction during that time period. This action of Muller, along with the failure of Snell to promote his discovery, greatly reduced the chances that those findings would complicate his attempt to garner support for his LNT single-hit model and its application to hereditary and cancer risk assessment. It also helped Muller achieve the Nobel Prize, allowing him the necessary international visibility to promote his ideologically driven ionizing radiation-related LNT-based paradigm.

Muller and mutations: mouse study of George Snell (a postdoc of Muller) fails to confirm Muller's fruit fly findings, and Muller fails to cite Snell's findings.

In 1931, Hermann J. Muller's postdoctoral student, George D. Snell (Nobel Prize recipient--1980) initiated research to replicate with mice Muller's X-ray-induced mutational findings with fruit flies. Snell failed to induce the two types of mutations of interest, based on fly data (sex-linked lethals/recessive visible mutations) even though the study was well designed, used large doses of X-rays, and was published in Genetics. These findings were never cited by Muller, and the Snell paper (Snell, Genetics 20:545-567, 1935) did not cite the 1927 Muller paper (Muller, Science 66:84, 1927). This situation raises questions concerning how Snell wrote the paper (e.g., ignoring the significance of not providing support for Muller's findings in a mammal). The question may be raised whether professional pressures were placed upon Snell to downplay the significance of his findings, which could have negatively impacted the career of Muller and the LNT theory. While Muller would receive worldwide attention, and receive the Nobel Prize in 1946 "for the discovery that mutations can be induced by X-rays," Snell's negative mutation data were almost entirely ignored by his contemporary and subsequent radiation genetics/mutation researchers. This raises questions concerning how the apparent lack of interest in Snell's negative findings helped Muller professionally, including his success in using his fruit fly data to influence hereditary and cancer risk assessment and to obtain the Nobel Prize.

Flavonoids commonly induce hormetic responses.

The present paper provides a new perspective of previously published findings by Siwak (Food Chem 141:1227-1241, 2013) which showed that 15 structurally diverse flavonoids reduced toxicity (i.e., enhanced cell viability) from hypochlorite using the MTT assay within a pre-conditioning experimental protocol, with each agent showing a similar biphasic concentration response relationship. We use this Commentary to point out that each of the concentration response relationships are consistent with the hormetic dose response. The paper of Siwak (Food Chem 141:1227-1241, 2013) is unique in that it provides a comparison of a relatively large number of agents using the identical experimental protocol.

Muller misled the Pugwash Conference on radiation risks.

The Pugwash Conferences have been a highly visible attempt to create profoundly important discussions on matters related to global safety and security at the highest levels, starting in 1957 at the height of the Cold War. This paper assesses, for the first time, the formal comments offered at this first Pugwash Conference by the Nobel Prize-winning radiation geneticist, Hermann J. Muller, on the effects of ionizing radiation on the human genome. This analysis shows that the presentation by Muller was highly biased and contained scientific errors and misrepresentations of the scientific record that resulted in seriously misleading the attendees. The presentation of Muller at Pugwash served to promote, on a very visible global scale, continued misrepresentations of the state of the science and had a significant impact on policies and practices internationally and both scientific and personal belief systems concerning the effects of low dose radiation on human health. These misrepresentations would come to affect the adoption and use of nuclear technologies and the science of radiological and chemical carcinogen health risk assessment, ultimately having a profound effect on global environmental health.

Nitric oxide and hormesis.

This present paper provides an assessment of the occurrence of nitric oxide (NO)-induced hormetic-biphasic dose/concentration relationships in biomedical research. A substantial reporting of such NO-induced hormetic effects was identified with particular focus on wound healing, tumor promotion, and sperm biology, including mechanistic assessment and potential for translational applications. Numerous other NO-induced hormetic effects have been reported, but require more development prior to translational applications. The extensive documentation of NO-induced biphasic responses, across numerous organs (e.g., bone, cardiovascular, immune, intestine, and neuronal) and cell types, suggests that NO-induced biological activities are substantially mediated via hormetic processes. These observations are particularly important because broad areas of NO biology are constrained by the quantitative features of the hormetic response. This determines the amplitude and width of the low dose stimulation, affecting numerous biomedical implications, study design features (e.g., number of doses, dose spacing, sample sizes, statistical power), and the potential success of clinical trials.

Hormesis mediates platelet-rich plasma and wound healing.

Platelet-rich plasma (PRP) has become an accepted and general wound healing approach with an extremely wide range of applications. Despite considerable diversity in the composition of platelet-rich plasma products that are applied in specific wound healing usage, it is widely recognised that such diverse platelet-rich plasma complex mixtures routinely display hormetic-like biphasic concentrations that are independent of the tissue treated and endpoints measured. The present paper is the first to place the area of platelet-rich plasma-biomedical research and applications within an hormetic framework. The platelet-rich plasma area is also unique as it represents the application of the hormetic concept to the issue of complex biological mixtures.

Sublethal chemical stimulation of arthropod parasitoids and parasites of agricultural and environmental importance.

An increasing number of studies have reported stimulation of various organisms in the presence of environmental contaminants. This has created a need to critically evaluate sublethal stimulation and hormetic responses of arthropod parasitoids and parasites following exposure to pesticides and other contaminants. Examining this phenomenon with a focus on arthropods of agricultural and environmental importance serves as the framework for this literature review. This review shows that several pesticides, with diverse chemical structures and different modes of action, applied individually or in combination at sublethal doses, commonly stimulate an array of arthropod parasitoids and parasites. Exposure at sublethal doses can enhance responses related to physiology (e.g., respiration, total lipid content, and total protein content), behavior (e.g., locomotor activity, antennal drumming frequency, host location, and parasitization), and fitness (longevity, growth, fecundity, population net and gross reproduction). Concordantly, the parasitic potential (e.g., infestation efficacy, parasitization rate, and parasitoid/parasite emergence) can be increased, and as a result host activities inhibited. There is some evidence illustrating hormetic dose-responses, but the relevant literature commonly included a limited number and range of doses, precluding a robust differentiation between sub- and superNOAEL (no-observed-adverse-effect level) stimulation. These results reveal a potentially significant threat to ecological health, through stimulation of harmful parasitic organisms by environmental contaminants, and highlight the need to include sublethal stimulation and hormetic responses in relevant ecological pesticide risk assessments. Curiously, considering a more utilitarian view, hormesis may also assist in optimizing mass rearing of biological control agents for field use, a possibility that also remains neglected.

Moringa induces its beneficial effect via hormesis.

Moringa oleifera, a traditional Indian herb, is widely known for its capacity to induce antioxidant, anti-inflammatory and other chemoprotective effects in a broad range of biomedical models. These perspectives have led to an extensive number of studies using various moringa extracts to evaluate its capacity to protect biological systems from oxidative stress and to explore whether it could be used to slow the onset of numerous age-related conditions and diseases. Moringa extracts have also been applied to prevent damage to plants from oxidative and saline stresses, following hormetic dose­response patterns. The present paper provides the first integrated and mechanistically based assessment showing that moringa extracts commonly induce hormetic dose responses and that many, perhaps most, of the beneficial effects of moringa are due to its capacity to act as an hormetic agent.

Confirmation that Hermann Muller was dishonest in his Nobel Prize Lecture.

In his Nobel Prize Lecture of December 12, 1946, Hermann J. Muller argued that the dose-response for ionizing radiation-induced germ cell mutations was linear and that there was ''no escape from the conclusion that there is no threshold''. However, a newly discovered commentary by the Robert L. Brent (2015) indicated that Curt Stern, after reading a draft of part of Muller's Nobel Prize Lecture, called Muller, strongly advising him to remove reference to the flawed linear non-threshold (LNT)-supportive Ray-Chaudhuri findings and strongly encouraged him to be guided by the threshold supportive data of Ernst Caspari. Brent indicated that Stern recounted this experience during a genetics class at the University of Rochester. Brent wrote that Muller refused to follow Stern's advice, thereby proclaiming support for the LNT dose-response while withholding evidence that was contrary during his Nobel Prize Lecture. This finding is of historical importance since Muller's Nobel Prize Lecture gained considerable international attention and was a turning point in the acceptance of the linearity model for radiation and chemical hereditary and carcinogen risk assessment.

Background radiation and cancer risks: A major intellectual confrontation within the domain of radiation genetics with multiple converging biological disciplines.

This paper assesses the judgments of leading radiation geneticists and cancer risk assessment scientists from the mid-1950s to mid-1970s that background radiation has a significant effect on human genetic disease and cancer incidence. This assumption was adopted by the National Academy of Sciences (NAS) Biological Effects of Atomic Radiation (BEAR) I Genetics Panel for genetic diseases and subsequently applied to cancer risk assessment by other leading individuals/advisory groups (e.g., International Commission on Radiation Protection-ICRP). These recommendations assumed that a sizeable proportion of human mutations originated from background radiation due to cumulative exposure over prolonged reproductive periods and the linear nature of the dose-response. This paper shows that the assumption that background radiation is a significant cause of spontaneous mutation, genetic diseases, and cancer incidence is not supported by experimental and epidemiological findings, and discredits erroneous risk assessments that improperly influenced the recommendations of national and international advisory committees, risk assessment policies, and beliefs worldwide.

Polyphenols in Inner Ear Neurobiology, Health and Disease: From Bench to Clinics.

There is substantial experimental and clinical interest in providing effective ways to both prevent and slow the onset of hearing loss. Auditory hair cells, which occur along the basilar membrane of the cochlea, often lose functionality due to age-related biological alterations, as well as from exposure to high decibel sounds affecting a diminished/damaged auditory sensitivity. Hearing loss is also seen to take place due to neuronal degeneration before or following hair cell destruction/loss. A strategy is necessary to protect hair cells and XIII cranial/auditory nerve cells prior to injury and throughout aging. Within this context, it was proposed that cochlea neural stem cells may be protected from such aging and environmental/noise insults via the ingestion of protective dietary supplements. Of particular importance is that these studies typically display a hormetic-like biphasic dose-response pattern that prevents the occurrence of auditory cell damage induced by various model chemical toxins, such as cisplatin. Likewise, the hormetic dose-response also enhances the occurrence of cochlear neural cell viability, proliferation, and differentiation. These findings are particularly important since they confirmed a strong dose dependency of the significant beneficial effects (which is biphasic), whilst having a low-dose beneficial response, whereas extensive exposures may become ineffective and/or potentially harmful. According to hormesis, phytochemicals including polyphenols exhibit biphasic dose-response effects activating low-dose antioxidant signaling pathways, resulting in the upregulation of vitagenes, a group of genes involved in preserving cellular homeostasis during stressful conditions. Modulation of the vitagene network through polyphenols increases cellular resilience mechanisms, thus impacting neurological disorder pathophysiology. Here, we aimed to explore polyphenols targeting the NF-E2-related factor 2 (Nrf2) pathway to neuroprotective and therapeutic strategies that can potentially reduce oxidative stress and inflammation, thus preventing auditory hair cell and XIII cranial/auditory nerve cell degeneration. Furthermore, we explored techniques to enhance their bioavailability and efficacy.

Hormesis: Transforming disciplines that rely on the dose response.

This article tells the story of hormesis from its conceptual and experimental origins, its dismissal by the scientific and medical communities in the first half of the 20th century, and its rediscovery over the past several decades to be a fundamental evolutionary adaptive strategy. The upregulation of hormetic adaptive mechanisms has the capacity to decelerate the onset and reduce the severity of a broad spectrum of common age-related health, behavioral, and performance decrements and debilitating diseases, thereby significantly enhancing the human health span. Incorporation of hormetic-based lifestyle options within the human population would have profoundly positive impacts on the public health, significantly reducing health care costs.

Hormesis: A General Biological Principle.

Hormesis drives biological modifications from cells to higher levels of biological organization and emerges as a general basic principle of biology, integrating evolution, ecology, medicine, physiology, toxicology, and public health.

Hormesis: Wound healing and keratinocytes.

Hormetic dose responses (i.e., a biphasic dose/concentration response characterized by a low dose stimulation and a high dose inhibition) are shown herein to be commonly reported in the dermal wound healing process, with the particular focus on cell viability, proliferation, and migration of human keratinocytes in in vitro studies. Hormetic responses are induced by a wide range of substances, including endogenous agents, numerous drug and nanoparticle preparations and especially plant derived extracts, including many well-known dietary supplements as well as physical stressor agents, such as low-level laser treatments. Detailed mechanistic studies have identified common signaling pathways and their cross-pathway communications that mediate the hormetic dose responses. These findings suggest that the concept of hormesis plays a fundamental role in wound healing, with important potential implications for agent screening and evaluation, as well as clinical strategies.

Hormesis: wound healing and fibroblasts.

Hormetic dose responses are reported here to occur commonly in the dermal wound healing process, with the particular focus on cell viability, proliferation, migration and collagen deposition of human and murine fibroblasts with in vitro studies. Hormetic responses were induced by a wide range of substances, including endogenous agents, pharmaceutical preparations, plant-derived extracts including many well-known dietary supplements, as well as physical stressor agents such as low-level laser treatments. Detailed mechanistic studies have identified common signaling pathways and their cross-pathway communications that mediate the hormetic dose responses. These findings complement and extend a similar comprehensive assessment concerning the occurrence of hormetic dose responses in keratinocytes. These findings demonstrate the generality of the hormetic dose response for key wound healing endpoints, suggesting that the hormesis concept has a fundamental role in wound healing, with respect to guiding strategies for experimental evaluation as well as therapeutic applications.

Hormesis is an evolutionary expectation: implications for aging.

This article argues that evolution and the concept of hormesis are biologically inseparable. It proposes that evolutionary processes led to the selection of inducible adaptive hormetic strategies that are necessary for wellbeing and survival. Hormesis has been demonstrated in essentially all organisms in which it has been studied from bacteria to humans, showing its highly conserved features. This evolution-hormesis integration should be a central feature in both understanding the biology of aging but also in ways to enhance improved health-based aging strategies.

Enhancing health span: muscle stem cells and hormesis.

Sarcopenia is a significant public health and medical concern confronting the elderly. Considerable research is being directed to identify ways in which the onset and severity of sarcopenia may be delayed/minimized. This paper provides a detailed identification and assessment of hormetic dose responses in animal model muscle stem cells, with particular emphasis on cell proliferation, differentiation, and enhancing resilience to inflammatory stresses and how this information may be useful in preventing sarcopenia. Hormetic dose responses were observed following administration of a broad range of agents, including dietary supplements (e.g., resveratrol), pharmaceuticals (e.g., dexamethasone), endogenous ligands (e.g., tumor necrosis factor α), environmental contaminants (e.g., cadmium) and physical agents (e.g., low level laser). The paper assesses both putative mechanisms of hormetic responses in muscle stem cells, and potential therapeutic implications and application(s) of hormetic frameworks for slowing muscle loss and reduced functionality during the aging process.

Low Levels of Contaminants Stimulate Harmful Algal Organisms and Enrich Their Toxins.

A widespread increase in intense phytoplankton blooms has been noted in lakes worldwide since the 1980s, with the summertime peak intensity amplifying in most lakes. Such blooms cause annual economic losses of multibillion USD and present a major challenge, affecting 11 out of the 17 United Nations Sustainable Development Goals. Here, we evaluate recent scientific evidence for hormetic effects of emerging contaminants and regulated pollutants on Microcystis sp., the most notorious cyanobacteria forming harmful algal blooms and releasing phycotoxins in eutrophic freshwater systems. This new evidence leads to the conclusion that pollution is linked to algal bloom intensification. Concentrations of contaminants that are considerably smaller than the threshold for toxicity enhance the formation of harmful colonies, increase the production of phycotoxins and their release into the environment, and lower the efficacy of algaecides to control algal blooms. The low-dose enhancement of microcystins is attributed to the up-regulation of a protein controlling microcystin release (McyH) and various microcystin synthetases in tandem with the global nitrogen regulator Ycf28, nonribosomal peptide synthetases, and several ATP-binding cassette transport proteins. Given that colony formation and phycotoxin production and release are enhanced by contaminant concentrations smaller than the toxicological threshold and are widely occurring in the environment, the effect of contaminants on harmful algal blooms is more prevalent than previously thought. Climate change and nutrient enrichment, known mechanisms underpinning algal blooms, are thus joined by low-level pollutants as another causal mechanism.

Cover up and cancer risk assessment: Prominent US scientists suppressed evidence to promote adoption of LNT.

This paper reports that William Russell, Oak Ridge National Laboratory (ORNL), conducted a large-scale lifetime study from 1956 to 1959 showing that exposure of young adult male mice to a large dose of acute X-rays had no treatment effects on male and female offspring concerning longevity or the frequency, severity, or age distribution of neoplasms and other diseases. Despite the scientific, societal and crucial timing significance of the study, Russell did not publish the findings for almost 35 years, nor did he inform governmental advisory committees, thereby significantly biasing decisions made during this period which supported the adoption of LNT for risk assessment. Of further significance, Arthur Upton, an ORNL colleague of Russell during this study and later Director of the US National Cancer Institute (NCI), was also fully knowledgeable of this study, its findings and its negative impact on the acceptance of LNT. Upton later worked along with Russell to publish these data (i.e., Cosgrove et al., 1993) to dispute the case-specific claim that children developed cancer because of the radiation exposure of their fathers as workers at the Sellafield nuclear plant. Thus, while Russell's data were available, but were not used to challenge the key radiation and leukemia paper of Edward B. Lewis, (1957) when LNT was being adopted by regulatory agencies, they were used in a major trial in the United Kingdom (UK) for the client (i.e., British Nuclear Fuels Plc) that hired Upton. While the duplicity of Russell's and Upton's actions is striking, the key finding of the present paper is that Russell and Upton intentionally orchestrated and sustained an LNT cover up during the key period of LNT adoption by regulatory agencies, thereby showing an overwhelming bias to enhance the adoption of LNT.