Dose-Response Revolution (Ed Calabrese) USofA

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This article was originally published in Encyclopedia of Biomedical Gerontology, published by Elsevier, and the attached copy is provided by Elsevier for the author's benefit and for the benefit of the author's institution, for non-commercial research and educational use including without limitation use in instruction at your institution, sending it to specific colleagues who you know, and providing a copy to your institution's administrator.

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Elsevier. vol. 1, Academic Press, pp. 519–528. https://dx.doi.org/10.1016/B978-0-12-801238-3.11442-4 ISBN: 9780128160756 Copyright © 2020 Elsevier Inc. All rights reserved Academic Press

Author's personal copy Dose-Response Revolution: How Hormesis Became Significant Edward J Calabrese, Department of Environmental Health Sciences, University of Massachusetts, Amherst, MA, United States © 2020 Elsevier Inc. All rights reserved.

Introduction The Dose Revolution: Part 1-Hormesis: Where It Started Dose Response Revolution: Part 2-Introducing the Linear Dose Response The Dose Response Revolution: Part 3-The Resurgence of Hormesis How Did the Hormesis Revolution Proceed?

Conclusion Acknowledgment References Further Reading

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Introduction The story of the dose response in biology and medicine seems like it should be simple and straight-forward. Yet, it is far from either, displaying a series of remarkably unique historical stages with each being controversial and highly contentious, in a struggle that has always been about what is the nature of the dose response in the low dose zone. It remains a problem yet to be resolved scientifically and/or politically and is still the object of Congressional Hearings in the United States Senate as recent as the fall of 2018 (Calabrese, 2018a).

With the emergence of the “modern” scientific era starting about 1880, the dose response concept found itself at the center of a war that would last almost another 50 years over who provides and controls medicine, its practice and drug enterprises. The battle was between homeopathy, a once powerful entity, and what would become modern Western traditional medicine (EJ Calabrese, 2005; Calabrese, 2011a). The dose response concept would later become a central player for low dose radiation risk assessment in the Manhattan Project when the United States produced the atomic bomb in World War II (Calabrese, 2011b) and in the subsequent high stakes game of above ground testing of nuclear weapons with worldwide radionuclide contamination. The dose response issue then quickly became the centerpiece of contemporary environmental risk assessment, being born again in the aftermath of Rachel Carson’s legendary book, Silent Spring. It is now renewing itself yet again, this time in the world of novel biopharmaceuticals and traditional herbal/Asian medicinal treatments that are being incorporated into modern Western medicine and lifestyles in an effort to enhance healthy aging.

This paper is about the history of the dose response and how its diverse scientific roads lead to hormesis. However, there have been major episodes, or stages in the history of the dose response and multiple battles fought over the nature of the dose response in the low dose zone, affecting careers, national economies, health and safety regulations, the testing of chemicals and drugs and whether, if and when neuron saving drugs will transform human health. As is the custom of all great complex mysteries this one will start at the beginning.

The Dose Revolution: Part 1-Hormesis: Where It Started While the term hormesis can be first traced to the undergraduate thesis of Chester Southam, an undergraduate mycology student at the University of Idaho in 1941 and then into the scientific literature 2 years later (Southam and Ehrlich, 1943), the “concept” of hormesis was born about 60 years earlier in the little academic town of Greifswald, in northern Germany. It started because the principal figure in this historic dose response drama, Hugo Schulz, a physician with excellent research experience in pharmacology and toxicology, was starting a professional career in 1882 at the University of Greifswald and needed a project to get his career off and running. What captured his interest was the aseptic surgery of Joseph Lister and the problems Lister was having finding a good antiseptic. So, Schulz started simply. He gathered about a dozen toxic chemicals that had disinfecting potential and assessed their capacity to disrupt and inhibit the metabolism of yeast. In his primitive laboratory setting, Schulz and his assistant systematically tested each of the agents using a rather impressive study design that employed multiple doses and followed the responses over time.

To his surprise the young Schulz noticed that each of these toxic agents acted in a biphasic manner, that is, at high doses they were inhibitory/toxic in a dose dependent manner as expected, but in the lower dose regions each became clearly stimulatory. Schulz figured that this stimulatory response was not biologically possible and that either he or his assistant had done something wrong.

They were forced to repeat the experiments many times, trying to figure out where they had made their subtle mistake that lead to the spurious low dose stimulation. Yet, time after time, the stimulation occurred. At some point in this process, they came to believe what the data and their eyes revealed, that each of these highly toxic agents behaved differently in the low dose zone, stimulating the metabolism of the yeast (Crump, 2003). Schulz would quickly share the findings at a local medical conference, but knew not what

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to make of these findings. Schulz was off to a very good start, as it appeared that he had discovered a new concept. Soon this hopeful picture would be turned upside down.

With his first research project completed there were many possible directions available as follow up. What did Schulz do next?

For a variety of reasons, but mostly cultural and familial, he closely followed the homeopathy literature. One study grabbed his attention. It was an 1884 study reporting that a homeopathic preparation called veratrine was successfully used to treat gastroenteritis (Calabrese, 2011b). The timing of this finding was nearly perfect since the famous Robert Koch, just down the road from Greifswald, had recently discovered and cultured the bacterium responsible for this human disease. Thus, Schulz obtained the culture and the drug veratrine and decided to test if the homeopathic medicine could actually kill the disease causing bacterium.

However, regardless of the dose, the bacteria were unaffected (Schulz, 1885). Schulz was forced to ponder whether the medicine actually worked as claimed by the homeopathic researchers or whether the disease resolution was simply a matter of random chance.

As for Schulz he simply let the issue intellectually resonant unresolved. The following year his thinking clarified with the aid of his professorial colleague Rudolph Arndt. They used their creativity to integrate all of the above story lines into the following belief: the veratrine actually was effective in treating the patients with gastroenteritis; however, the mechanism of action was not via direct killing of the bacteria but via the upregulation of defense mechanisms that helped fight off the infection. To support this scheme they now integrated the yeast data. They claimed that the veratrine and many (perhaps all) other homeopathic drugs act at low doses to stimulate needed adaptive responses to fight off biological, chemical and other health threats. With this integration, Schulz tied together the clinical observations and placed them within a dose response context. Schulz then made a big leap, claiming that he had just discovered the explanatory principle of homeopathy (Crump, 2003). As we will learn, this was either the end or the beginning of Schulz’s professional life.

From the moment Schulz went public with this assertion, the life of this young, industrious and quiet man became highly controversial, as he had sided with the “enemy” in the battle between what we now call traditional medicine and its opponent, homeopathy. Now, about 135 years later it is easy to perceive the significance of this historic battle, which pitted a much stronger Homeopathy against a far weaker “traditional” medicine as compared to the totally reversed positions throughout the latter half of the 20th century and now into the 21th century. At the time of the Schulz discovery, there was a very intense philosophical, medical and sociological confrontation between these two powerful medical economic entities with both seeking true dominance over the other.

Traditional medicine wanted to emasculate homeopathy and if that meant refuting, marginalizing, and even misrepresenting the position of the alleged opponent then it would be done. In this case, key leaders in traditional medicine thought that by destroying Schulz’s scientific reputation and his dose response explanatory principle of homeopathy they would both damage homeopathy and enhance their likelihood of success. Schulz would simply become collateral damage in this complex, intense and far reaching conflict. In fact, Schulz was soon marginalized by his Greifswald Medical School colleagues, quickly learning that his proclamation would have profound effects on his career aspirations, as Greifswald at that time, was a routine academic stepping-stone to more influential academic centers and achievement. Not only was his career placed on a permanent hold (i.e., remaining there until he died in 1932) but he and his new dose response theory would be on the receiving end of substantial and often unfair criticism. The criticisms would have great influence since they were delivered by the upper echelon of British pharmacology professors as most noticeably lead by Alfred J. Clark, the Edinburgh professor, whose textbooks revolutionized both pharmacology and toxicology with a reach extending to the present (Clark, 1937). These actions of key leaders against Schulz have now been well documented (EJ Calabrese, 2005; Calabrese, 2011a).

While it is very easily shown that Schulz did not accept the homeopathic belief that there was biological activity below Avogadro’s number (Bohme and Schulz, 1986), Clark would nonetheless deliberately misrepresent his stated positions in a successful effort to damage his scientific reputation (EJ Calabrese, 2005; Calabrese, 2011b). Clark would also ignore valid scientific findings supporting the Schulz position while bringing focus to more trivial and less reproducible findings. At the same time Schulz was not a fighter but a stoic researcher who tended to more quietly perform his academic duties. When Schulz died, a longtime pharmacological colleague at Greifswald would write an extensive sympathetic scientific obituary pointing out the efforts that were made by leaders in traditional medicine to destroy Hugo Schulz’s professional reputation and how this talented and independent thinking scientist had to endure constant professional and personal abuse over a 50-year career. mostly enduring in silence (Wels, 1933).

The “taking down” of the intellectual leader (i.e., Hugo Schulz) of the opposition was the strategy of traditional medicine. It seems that part of their strategy was that by destroying the professional career of one as talented as Schulz it would prevent other such challenges from arising.

Despite the challenges and marginalization facing Schulz, he and his findings did impact broad areas in biology. This is seen with the undertaking of numerous dissertations and other research in the areas of plant biology, microbiology and entomology assessing biphasic dose response relationships (Calabrese and Baldwin, 2000a,b,c,d,e). These areas lent themselves to the study of hormesis since researchers could assess a large number of doses in an efficient manner as would not be the case with more cumbersome and expensive whole animal rodent studies. Likewise, cell culture would not be developed in any serious manner for nearly the next 70–80 years (Calabrese, 2013a). Considerable support for Schulz’s biphasic dose response was reported, mostly by researchers not involved in the homeopathy-medicine dispute. The findings would be extended to a broad range of chemicals as well as ionizing radiation. One telling feature was that a research protégé of Robert Koch, Ferdinand Hueppe, extended Schulz’s findings to bacteria, pleading that Schulz’s results were both reproducible and generalizable. In fact, he decided to rename the phenomenon after himself, calling it Hueppe’s Rule (Calabrese, 2011b).

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Despite the diverse and growing support of the Schulz findings, the biphasic dose response, then called the Arndt-Schulz Law or Hueppe’s Rule failed to thrive. This was mostly due to the success of Clark and others in biomedical domains to ridicule and suppress Schulz’s activities and to block this idea from curricula, textbooks and research support. This is precisely the reason why pharmacologists and toxicologists educated for nearly the entire 20th century (including the author) were not introduced to the concept as it was excluded from curricula and the textbooks. This is an example of data censoring, a type of intellectual brainwashing that occurred in western democracies where intellectual freedom was supposed to be cherished. However, in this case, the tyrannical entity was traditional medicine that also came to influence vast aspects of federal and state governments, educational institutions as well as the print media. Thus, the medical complex became a powerful force that had the capacity to nearly kill a fundamental idea in biology, hormesis. In fact, the reappearing biological reality of hormesis may be the principal reason why the hormesis concept survived in this hostile scientific-medical climate.

Traditional medicine also knew that it had been scooped on the topic of dose response by their opponent (i.e., homeopathy) such that it had to now adopt its own dose response model. This proved to be easy as they adopted the threshold dose response. The threshold dose response resonated with common sense and routine daily observations. It was also readily seen in experimental studies, especially when using few and relatively high doses. This threshold dose response view by traditional medicine became a general principle in pharmacology and toxicology from the early 1920s onward as homeopathy was quickly losing standing and the scientific strengths of traditional medicine were emerging. In fact, in the United States there were 23 schools of homeopathy in 1900 but only two remained by the early 1920s (Calabrese, 2011b). In the battle for dominance the winner was clearly traditional medicine and the losers were homeopathy, Schulz and the biphasic dose response model.

As the scientific community entered the 1930s the threshold dose response had become a central belief, despite the fact that Schulz’s biphasic dose response was still being reported by many biologists. However, the findings were never adequately synthesized and integrated. Further, essentially all key researchers who followed in the intellectual footsteps of Schulz from the 1880s to late 1930s had their careers diverted, with most moving into various types of administration, leaving the biphasic dose response question to remain unsettled (Calabrese, 2009). Furthermore, this grouping of researchers never organized themselves, losing the opportunity to galvanize their ideas and to chart a research trajectory. They were mostly a band of independent researchers whose findings appear insufficiently connected and integrated with similar research developments. This lack of organizational leadership and focus would impede progress on and acceptance of the biphasic dose response.

Dose Response Revolution: Part 2-Introducing the Linear Dose Response Despite the striking success of traditional medicine to establish the threshold model, it would be unexpectedly challenged by the radiation genetics community concerning the capacity of ionizing radiation to induce gene mutations. Following his seminal publication in 1927 that X-rays induce transgenerational phenotypic changes in the fruit fly, presumably via gene mutation, Hermann J. Muller proposed that this occurred via a linear dose response (Calabrese, 2013b). He claimed this to be the case under the belief that all genetic damage was non-repairable, irreversible, cumulative, and therefore the dose response would be linear, even down to a single ionization. Muller would call this the Proportionality Rule (Calabrese, 2013b). However, the thinking of Muller was not well received by the medical community, even though one may have thought that the community of radiation geneticists were on the same intellectual team. At this time, this was not the case and a major schism developed. The medical community held strongly to their threshold policy and resisted attempts by the radiation community to change radiation exposure standards to a linear perspective. This was achieved by excluding radiation geneticists from key committees or ensuring that they would never have enough votes to change a policy, exposure standard or medical practice. The tensions between the physician lead threshold dose response perspective and the linearity led radiation geneticists was very tangible (Calabrese, 2015, 2018b, 2019; Luckey, 1991). While it took nearly three decades, Muller and his radiation geneticist colleagues were finally able to circumvent the resistance of the medical community, getting no less than the US National Academy of Sciences (NAS) in 1956 to recommend exactly what Muller and his colleagues had long wanted, a switch from the threshold dose response to the linear non-threshold-single hit model for mutations and soon for cancer (Anonymous, 1956). Making the switch to linearity did not occur by chance and persuasion as it was the product of fear of radiation in the aftermath of the dropping of the atomic bombs to end World War II, the subsequent above ground testing of nuclear weapons and radionuclide contamination heightened Cold War tensions between the United States and the Soviet Union, and finding a way to stack the deck so that the radiation geneticist perspective would finally prevail.

In response to this global radiation predicament the Rockefeller Foundation funded a major initiative by the NAS to assess nuclear contamination of the oceans, agriculture, and atmosphere and how to deal with these new challenges and their medical and societal implications. A key feature of this initiative was that the president of the Rockefeller Institute for Medical Sciences and the president of the National Academy of Sciences was the same person, Dr. Detlev Bronk. Thus, Bronk used the Rockefeller Foundation to fund Bronk the president of the NAS. This process allowed Bronk to create a unique Genetics Panel that would be separate from a Medical Panel. He created an explicit Genetics Panel, a substantial proportion of whom had been largely funded in their academic research by the Rockefeller Foundation (RF), essentially stacking the deck with those geneticists whose support for linearity were well known. Thus, it was pretty much known that this grouping of geneticists was going to recommend a switch to a linear dose response even before the first meeting of the Genetics Panel was officially convened. In addition, Bronk handpicked the chair of the Panel, the longtime Director of Research at the RF, Warren Weaver, a non-geneticist who had long distributed research funds to many of the Panel members. In one of their early NAS meetings the Genetics Panel asserted the equivalent of a radiation

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geneticist creed, that all genetic damage was irrepairable, irreversible, and cumulative. These characteristics, they believed, would result in a linear dose response. Weaver would reinforce these conclusionary beliefs, with an explicit temptation (documented in Panel transcripts) that large amounts of continuing funding would be made available should their report be in line with RF directives. In fact, there was little for the Panel to do once their proclamation was made (EJ Calabrese, 2005; Calabrese, 2018b, 2019).

Even though the Panel was uniform in their belief in linearity, they were concerned whether other scientists and the general public would accept their transformative linearity policy recommendations. Weaver therefore challenged the geneticists to estimate the number of adverse genetic effects in subsequent generations of US residents assuming a given dose of ionizing radiation to the gonads. This was an important tactic since the Panel was comprised of a diverse set of geneticists: bacterial, insect, mouse, clinical, population-based and others. It was felt that if their estimates closely converged it would add great confidence to their radiation mantra and help ensure the acceptance of their policy recommendations. They were asked in early February 1956 to provide their detailed written assessment in a month. Of the 12 geneticists on the Panel nine agreed and provided their individual assessments within the agreed upon time. The remaining three generally felt that this was an impossible assignment as there was simply too much uncertainty and reliable estimates could not be provided (Calabrese, 2019).

When the nine estimates were returned to panelist James Crow for collating and organizing the responses he noticed a serious problem. These estimates displayed enormous quantitative variation such that there was little agreement amongst the experts even though they were constrained to assume that the dose response was linear in the low dose zone, something that would have helped to assure estimate convergence but even this biasing of the results did not help enough. Crow wrote that if their lack of agreement were to be shared with the public their risk assessment recommendations (i.e., linear dose response) most likely would not be accepted. Apparently, on his own, but without any objections, Crow excluded the three lowest risk estimates, drastically reducing the variation. However, the remaining six estimates still showed a 750-fold uncertainty range. In a second example of altering the scientific record, Crow simply changed the number from 750 to 100. While it is easy to see evidence of Crow as the leader of this scientific misconduct, the entire committee was fully complicit as they allowed the report to be published with the dishonesties in the journal Science while also voting not to share the data with the scientific community. This vote of the Panel was then forwarded to Bronk, thereby linking the President of the NAS with the unethical activities of the Genetics Panel. With one of their Panel members on the Science journal Editorial Board (i.e., Bentley Glass), publication of this flawed manuscript was a simple fiat (Calabrese, 2015, 2019).

The NAS Genetics Panel LNT recommendation was publicized very extensively, with the report making front-page stories in major US outlets like the New York Times, Washington Post and others. The publicity would soon result in US Congressional Hearings where the disinformation game plan would be continued. The bottom line is that the LNT recommendation was soon adopted in the US and in many other countries based upon the high credibility of the NAS. Thus, the LNT policy was the product of deliberate falsification of the research record. Well before the dishonest deed by the NAS Genetics Panel, the seeds of this scientific deception was started by radiation geneticist leaders such as Hermann Muller and Curt Stern, who misrepresented the mutation data during the Manhattan Project to ensure support for an LNT perspective, with this culminating with a brazen Muller deliberately deceiving his Nobel Prize audience on December 12, 1946 when he strongly asserted there was no longer any possibility to support a threshold model, after having just seen the strongest study yet conducted on the issue with its data showing a threshold response. The above stories have been documented in considerable detail and the reader is directed to the following references (Calabrese, 2011b, 2015, 2019).

Linearity would get a scientific booster shot some 16 years later when yet another NAS Genetics Committee would reaffirm it, while at the same time switching the basis for LNT from the fruit fly to the mouse model based on the massive research of William Russell with more than 2 million animals using the specific locus test (Calabrese, 2017a,b). Russell’s work was important for it provided strong support for a significant DNA repair function and the existence of a clear threshold response in oocytes at 27,000 times greater than background radiation rate. However, the Committee retained the LNT recommendation when the male failed to return to control values although it clearly demonstrated a strong DNA repair function in these dose rate studies but a threshold had not been achieved at the dose rates used. While it may well have been reasonable to assume that males would show a threshold at a lower dose rate, the Committee opted to retain LNT. This recommendation by the NAS would prove to be pivotal as 5 years later EPA would base its LNT policy for ionizing radiation and chemical carcinogens on the scientific findings of Russell and the recommendation of this NAS Genetics Committee and continue this recommendation to the present time (Calabrese, 2019, 2017a,b).

The story of the Russell data and the reaffirmation of LNT by Biological Effects of Ionizing Radiation (BIER) I committee report in 1972 developed a signification twist some 25 years later (Calabrese, 2017a,b). A long time Department of Energy (DOE)/Oakridge National Laboratory geneticist, Paul B. Selby, and colleague of Russell (former Ph.D. student of Russell) discovered troubling irregularities in portions of the control group data in the massive mouse studies used to support LNT. Follow up secretive investigations

by Selby lead him to assess whether the irregularities were systematic, possibly deliberate (hence the secretive investigation) and of scientific significance, affecting its widespread risk assessment applications. Concerned with sharing these findings with the Oakridge administration, Selby met with the top leadership at the DOE, revealing his findings. This lead to follow up investigations including the use of an external panel of national and international experts who questioned the Russells and Selby. Documents from those hearings revealed that the Expert Panel concluded that the Russells had made serious errors, which needed to be corrected and directed the Russells and Selby to correct the record in the scientific literature. In 1996, the Russells reported that their control group had been “off” or in error by some 120%, a massive error (Russell and Russell, 1996). As for Selby (1998) he concluded that the magnitude of the error was far greater, more than several fold. These corrections were published in leading

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journals in a manner that was extremely technical and devoid of personal animosities as well as its societal implications. Thus, it was difficult for the field to sense the significance of these actions. However, 20 years later, I learned of this controversy, obtaining considerable background information, interviewing Selby for many hours and pieced the story together. I then applied the Russell and Selby corrections to the 1972 data used by the NAS to derive their influential LNT recommendation. What emerged from these “data adjustments” was that with the more modest Russell correction the female data would have shown an hormetic response while the male would have shown a threshold. The Selby corrections for females and males suggested hormesis (Calabrese, 2017a,b). Thus, the LNT recommendation, which was adopted by EPA and many countries, was based on an error.

The Dose Response Revolution: Part 3-The Resurgence of Hormesis Within this historical context, the biphasic dose response would be reported in numerous scientific publications in the half-century following Schulz’s discovery (Calabrese and Baldwin, 2000a,b,c,d,e). These findings never received very serious consideration nor did investigators have much of a clue as to how to study this phenomenon with respect to study design, statistical power issues, reproducibility as well as mechanism. The Schulz phenomenon would also receive a name change in 1943 by Southam and Ehrlich (1943) to that of hormesis, meaning to excite. However, it took about 30 more years (i.e., mid to late 1970s) for scientific momentum to begin to switch toward hormesis as lead by Luckey (1980), with radiation, and Stebbing (1982) in marine toxicology. These two individuals provided a sustained credible experimental focus to the topic and should be credited with inspiring/laying the groundwork for the modern hormesis dose response revolution that is currently occurring. This resurgence would gain traction when Luckey’s 1980 book on radiation hormesis inspired the first radiation hormesis conference in August 1985, with the proceedings published 2 years later in the journal Health Physics.

From the time of the Southam and Ehrlich hormesis name change in 1943, there is almost no mention of the term hormesis in the Web of Science even though listed as a key word in this database by 1946. The leadership of Luckey and Stebbing, therefore, was not dramatic as the number of citations on hormesis or hormetic in the Web of Science was only about 10–12 citations per year for the entire decade during the 1980s. However, in 2018 alone, the number of such citations is greater than 10,000, more than a 1000fold per year increase. suggesting a type of scientific revolution. What happened to turn the scientific interest in the hormesis concept around?

While scientific revolutions are complex and multi-dimensional, the story of hormesis in many ways is linked to me and my near singular focus to this topic since the first Hormesis conference in 1985, especially since 1990. My involvement was unique since I had discovered hormesis for myself in 1966 as an undergraduate student in a plant physiology class and would go on to perform some 38 experiments on the topic during this several year period. My first presentation on hormesis was at an undergraduate research conference at Yale University in the spring of 1967. In fact, when I published on this biphasic dose response I had yet to know of the term hormesis (Calabrese and Howe, 1976). However, my return to the topic nearly 20 years later was significant since I had two decades of learning as an academic scientist on how to write and publish articles and books and had made substantial personal and professional contacts that could be critical. Importantly, I had a tenured faculty position at a major University and this allowed me to explore a new area without risking my position. In many ways, this was the perfect scientific storm.

How Did the Hormesis Revolution Proceed?

My renewed involvement in hormesis was inspired by a debate in the journal Science between Sagan (1989) and Wolff (1989) on hormesis, two individuals who played a major role in the 1985 hormesis conference. Upon reading the debate, it seemed that they just rehashed the conference proceedings, losing a great opportunity for intellectual leadership and inspiration. So, I called Sagan and expressed this perspective and suggested the need to more productively address the hormesis question and how to move it forward scientifically.

I knew that as important as Luckey and Stebbing were to the hormesis story their actions had not been very successful. This was mostly because they acted as individual scientists, with no effort to build an organizational framework. Thus, their efforts simply did not transform the field. They seemed like many similar hormetic researchers in past decades; they created some interest but had no plan on how to proceed. They lacked an organization and a strategy. This would need to change.

The conversation with Sagan directly led to a May 1990 meeting, which restarted and refocused interest on hormesis and represents the start of the hormesis revolution. I invited 16 leading US scientists (including Sagan) from government, industry and academia to UMass/Amherst. After several days we decided to create an organization called BELLE (Biological Effects of Low Level Effects-the acronym was created by Don Hughes of Proctor and Gamble) whose mission would be to learn more about hormesis, its history, occurrence, mechanisms and its generality and to share these developments with the scientific community. This effort would be science based, broadly educational and non-ideological and with a broad focus on chemicals, radiation and pharmaceutical agents. The effort would be based at the University of Massachusetts and be funded by government and industry.

The BELLE initiative tried to be expansive, reaching out to the biomedical and toxicological communities, exploring the capacity for hormesis to affect many aspects of human health and disease. The hormesis concept and message resonated almost immediately in areas such as neuroscience, aging, exercise science, immunology, and cancer biology. These developments lead to invitations to make presentations on hormesis to pharmaceutical and chemical organizations, federal regulatory agencies, universities, and major

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conferences. A key goal was trying to interest scientists to evaluate hormetic hypotheses in prospective studies and to interest regulatory agencies in hormesis, and its potential role in risk assessment.

My engagement with hormesis became a dominating theme. I would devote about 70 technical hours per week for nearly 52 weeks per year over the past nearly 30 years, providing a driving force in the hormesis revolution. This led to my publishing over 20 papers per year on hormesis in peer-reviewed journals, for the past 20 years, many being extensively cited in Web of Science.

Likewise, multiple leading textbooks sought out chapters on hormesis, allowing this idea to become part of formal university curricula through multiple editions.

The reason why the hormesis concept had transformed my professional life was because of its generality, potential significance in evolutionary biology, agriculture, public health and medicine and that this concept had been missed and in fact deliberately shunned by the dominant scientific establishment for more than a century. However, this understanding did not come all at once but continued to evolve as more insight was gained into its biology, evolutionary significance, and historical foundations.

What were the conceptual steps that lead to hormesis becoming significant?

I was determined to learn from past mistakes or oversights, starting with Schulz, all the way to Luckey. what had they missed or had done wrong. while it was easy to place blame for the failure of hormesis to gain traction on the battle between homeopathy and traditional medicine and the unfairness of the lifetime attacks on Schulz and others, it was also true that these individuals, despite their efforts, still failed to be generally convincing. I had to figure out a new scientific strategy. to objectively assess whether hormesis was both real and broadly significant and, if so, then to challenge the scientific community to take the same learning journey. but how to do it?

My initial belief was that Luckey and Stebbing failed to provide a priori objective criteria to define an hormetic dose response and how to apply it. As a result, I came to the conclusion that these leaders were susceptible to criticism that some of their scientific conclusions on hormesis were subjective, susceptible to bias. Luckey’s books were also written prior to the determination of the underlying hormetic mechanisms, thus further eroding confidence. Since he was trying to establish a highly marginalized dose response concept, the personally forceful Luckey needed to have high standards that could withstand rigorous evaluation, considerable skepticism and strong institutional and historical bias. With such odds stacked against him, and without a carefully designed and executed strategy, Luckey was principally successful in converting the “believers,” making only a marginal dent in the rest of the field. Thus, despite several substantial efforts the Luckey initiative failed to make hormesis significant. Further undermining chances of success was that he and Stebbing failed to create a diverse scientific organization/network that could extend their message and credibility to a wide range of scientific, governmental and industrial groups, reducing their effectiveness.

Having thought long on the lessons of Luckey I decided that the first step to becoming “significant” was create objective and valid criteria to assess whether a dose response was hormetic or not. The first problem was that there were no gold standard criteria or biological markers for hormesis like there was for mutation.

The key therefore was to determine whether specific biphasic or hormetic dose response curves would be a reproducible expectation. A set of a priori objective dose response evaluative criteria were created based on a weight of evidence framework. Having carefully studied numerous governmental and other weight of evidence procedures for cancers, mutations, reproductive toxins and other endpoints, this conceptual framework was then applied to the problem of hormesis. The effort would lead to the creation of the Hormetic Data Base where each dose response would be evaluated with the same rigorous objective criteria and receive a numerical score, providing a quantitative estimate of the strength of an hormesis interpretation. This approach was created to eliminate subjectivity such that the scores obtained and the judgment made would be independent of the person doing the evaluation. This goal was achieved during the piloting of the data base evaluation process. The capacity to be reliably objective was an important first step on the road to potential significance.

Following this effort, we wanted the hormetic data base evaluated by the toxicological community with application to many hundreds of examples of hormesis. Several papers based on these efforts passed peer review, supporting the premise that we were on the right track. The next goal was to greatly expand this effort to assess how general the hormesis concept was. That is, did it seem evolutionarily based, would it occur in all types of biological systems, from microbes to plants to invertebrates to vertebrates, all cells types, in vivo and in vitro and at all levels of biological organization and across the lifespan. If this were the case, it could represent a further major step forward.

Such an effort would take several years to build a robust data base. During this hormesis learning decade of the 1990s there was no serious interest in hormesis as a general biological concept by major federal, industrial or academic entities. Yet, this created a good personal opportunity to learn, make mistakes, formulate new ideas in an undisturbed and non-competitive academic playground that was getting prepared for center stage. Nonetheless, there had been an intermittent but growing interest in the role of hormesis in aging, including interests by Masoro (1998) (University of Texas at San Antonio) and Ronald Hart (Turturro et al., 2000) at the US FDA’s National Center of Toxicological Research. These hormesis-biogerontology research perspectives would become lead by Suresh Rattan in Denmark as both Masoro and Hart would shortly retire. In a similar fashion, the field of neuroscience would also see interest in hormesis and its therapeutic applications for various neurodegenerative diseases. In this context, I became aware of the research of Mark Mattson, US National Institute for Aging (NIA), and Vittorio Calabrese (not at relative) from Italy. Ron Mitchell (Canadian Nuclear Industry), Shu Zheng Liu (China), and Shuji Kojima (Japan) and their students had expanded upon the Luckey radiation initiative with important mechanistic findings. There were other leaders in the areas of exercise science, ecological toxicology, microbiology, plant science, and other domains. These researchers were also prominent in their fields, with interests converging with mine in significant, yet independent ways. These contributions suggested an inter-disciplinary resurgence of interest in hormesis.

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More quantitative evidence that the efforts of the BELLE initiative were affecting the scientific community was that in the year 2000 the number of citations on hormesis or hormetic in the Web of Science had reached 400. These developments also lead to the need to clarify the scientific understanding of hormesis. This resulted in two papers, Calabrese and Baldwin (2002) as written from a toxicological perspective and then a few years later by Mattson (2008) from a biomedical perspective. Both of these papers have been cited over 400 times in the Web of Science. Of significance, we emphasized that hormesis could result in beneficial or harmful effects depending on the specific research conditions and endpoints. We also addressed the generality of hormesis and its quantitative features. The paper by Mattson was particularly helpful in translating hormetic findings for public health and therapeutic application.

Even though more than a century had passed since the original discovery of Schulz, no systematic analysis of the hormetic dose response had been undertaken. As a result of the vastly expanding hormetic data base we discovered that the magnitude of the hormetic stimulation was typically modest with the vast majority of maximum stimulatory responses being less than twice the control group value and most of these being only about 30–60% greater than the control. This was independent of biological model, endpoint, inducing agent, potency of the inducing agent, and level of biological organization. This was the case whether the stimulation occurred via a direct stimulation or via an over compensation to a disruption in homeostasis (Calabrese and Baldwin, 2001, 2003). These findings suggested that there was a limitation placed upon the magnitude of the stimulation and that this must have been highly conserved in evolution since this pattern was similar from microbes to man. This impressive biological regularity further suggested that the magnitude of the hormetic dose response may represent a quantitative index for a very fundamental type of biological plasticity (Calabrese and Mattson, 2011, 2017). If this were the case, the hormesis concept would be a fundamental biological principle with considerable evolutionary, biological, and biomedical implications.

These findings were superimposed on observations that hormesis occurs across a very broad spectrum of biological systems, from plant to animal and small to large, from aquatic to terrestrial. The hormetic response also affected a wide range of functions, including normal biological/physiological maintenance activities as well as mediating adaptive responses. We determined that many receptor systems that control and regulate most vital functions do so via hormetic-biphasic dose response relationships following the same quantitative features of the hormetic dose response. However, no one had previously reported that relationship.

This meant that hormetic dose responses were controlling key regulatory features of numerous receptor based processes in all cell types, mediating effects at the cell, organ, and organism levels. It became therefore progressively clear that hormesis was a fundamental biological concept that had been overlooked by traditional medicine.

These insights then spurred a broad consideration of whether hormesis might be present in preclinical studies used in drug development. Such investigations revealed that indeed hormetic dose responses were almost always reported in preclinical drug studies for anxiolytic (Calabrese, 2008a), anti-seizure (Calabrese, 2008b), memory and drugs (Calabrese, 2008c) from a host of other clinical areas (e.g., bone strengthening, growing hair, wound healing) as well (Calabrese, 2008d). It was also found that hormetic responses occur for a very large proportion of antitumor drugs regardless of the tumor cell line tested on. This was also the case of antibiotics as well. In these latter two cases the low doses enhanced the proliferation of tumor cells (Calabrese et al., 2006, 2008) and harmful bacteria in an hormetic manner, respectively (Calabrese et al., 2010).

A major development in the hormesis story was estimating the frequency of hormesis in the pharmacological and toxicological literature. This question was also rolled into the issue of which dose response model could best predict low dose effects, the threshold, linear or hormetic model. We first searched for evidence for how the scientific community validated the long dominant threshold model. No evidence was found that anyone had ever formally attempted to test the capacity of the threshold model to make accurate predictions in the low (i.e., below threshold) dose zone. This was a striking finding since it meant that the model used by all countries for human risk assessment had never been validated. We then obtained multiple large and biologically diverse data sets and compared which three models did the best job estimating responses in the low dose zone using a priori entry and evaluative criteria. In a series of studies the hormetic model far outperformed its two dose response model rivals. Thus, the model that had been rejected many decades earlier by the scientific establishment performed best and the only one that did an effective job (Calabrese and Baldwin, 2001, 2003; Calabrese et al., 2006, 2008).

In a concurrent fashion, we also developed the first estimate of the frequency of hormesis in the pharmacological and toxicological literature. Using rigorous a priori entry and evaluative criteria we determined that of the dose responses satisfying the entry criteria 40% satisfied the evaluation criteria, some 2.5-fold more than its closest rival the threshold model (Calabrese and Baldwin, 2001, 2003). This was the first time that an hormesis frequency was reported in the general pharmacological and toxicological literature. These developments were crucial since they not only established a generalizable frequency of hormetic responses using very demanding standards but also that hormesis outperformed the two models used by regulatory agencies in their risk assessment activities (Calabrese et al., 2006, 2008).

Despite these advances in the understanding of what hormesis is, and its evolutionary foundations, molecular biology is principally focused on mechanism. During the 1990s the tools to clarify hormetic mechanisms were very limited. Despite many thousands of reproducible biphasic dose responses, hormesis needed a firm mechanistic basis to be credible. By the early 2000s advances were being made in identifying and filling in numerous steps in cell signaling pathways mediating hormetic dose responses. As a result, in 2013 I published an integrated assessment of hormetic mechanisms down to the receptor and cell signaling pathway for 400 different hormetic dose responses (Calabrese, 2013c). This was perhaps the last major lingering hurdle that had long affected a broad acceptance of hormesis.

Establishing the mechanistic foundations of hormesis was important for placing it on par with other leading biological concepts.

These developments provided the capacity to explain in specific terms how dose responses acted in a biphasic manner. Biphasic

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dose responses could occur in all systems via different receptors and cell signaling pathways. Yet, despite the plethora of different proximate mechanisms all displayed the same qualitative and quantitative biphasic dose response features. Hormesis was therefore a basic evolutionary strategy, used by all biological systems with tailored regulatory receptor and signaling procedures to mediate a highly conserved dose response strategy.

Further developments subsequently emerged when I discovered that the complex of adaptive responses in radiation and chemical preconditioning biology also uniformly conformed to the quantitative features of the hormetic dose response. We published a comprehensive assessment of this area under the title: “Preconditioning is Hormesis,” providing extensive historical, biomedical, and mechanistic findings documenting this relationship (Calabrese, 2016a,b).

Over the past nearly 30 years I have learned that hormesis is central to biology. All biological systems use dose responses and regulate their activities in the context of hormetic dose responses. Hormesis mediates routine, ongoing maintenance of biological processes as seen with essentially all receptor systems but also adaptive responses that protect all cells and biological systems from physical and chemical induced damage from normal aging due to endogenous and external threats via preconditioning and postconditioning and other resilience enhancing processes. Hormesis reveals an evolutionary strategy for survival and performance optimization. This hormetic based optimization process uses the concept of plasticity to mediate the allocation of biological resources on common cell signaling paths for routine and stress-based adaptive processing (Calabrese and Mattson, 2011, 2017).

In a very practical manner, hormesis takes this response maxima by which drugs can improve biological performance and then imposes this 30–60% constraint on pharmaceutical companies and others attempting to design and conduct clinical trials. That is, if the maximum expected increase of a drug treatment is in the hormetic 30–60% range this affects the study design, including the number of doses, sample size, and statistical power. Failure to understand hormesis will affect whether a drug passes the clinical trial or not. This can be applied to the concept of increasing memory, strengthening bone, growing hair or trying to extend life. These parameters are bounded by the limits of biological plasticity that are described by the hormetic dose response and regulated by hormetic mechanisms. These constraints are also seen when trying to use multiple agents to act synergistically to obtain responses that far exceed the 30–60% hormetic maxima. However, the hormetic maximum appears to act like the well-known pharmacological ceiling effect (i.e., the ceiling effect is simply the hormetic maxima), with redundant controls to ensure that responses stay within their plasticity bounds, preventing synergistic responses beyond plasticity limits.

Conclusion Hormesis became significant the hard way, it was a concept that was the target of historical antipathies between homeopathy and what is now call traditional medicine. The discoverer of hormesis, Hugo Schulz, made a terrible historical blunder by claiming that his biphasic dose response provided the explanatory principle of homeopathy. Given that homeopathy was profoundly defeated in this economic and scientific battle by traditional medicine the hormetic-biphasic dose response had a decidedly disastrous entry into the scientific world. In fact, traditional medicine would never ease up on the opposition and neither homeopathy nor medicine could discern what hormesis was, how to study it and wherein its value might lie. It became an orphan dose response concept with an unrelenting enemy who nevertheless had long forgotten what the fight originally was about or that there actually had been a fight.

This lack of historical understanding (and memory) has ironically made the hormetic dose response challenge even more difficult to resolve. Thus, the road to significance for hormesis was unique, unfair, unpredictable and yet nonetheless, almost inevitable since science would be forced to eventually assess low doses and evolutionarily based adaptive responses. Thus, hormesis was marginalized for a long time but never knocked out as scattered researchers continued to report hormetic responses in a haphazard fashion while failing to understand its importance.

It took about 30 years from the time of the last hormesis failed resurgence (i.e., the Luckey/Stebbing attempt) for the significance of hormesis to be revealed by scientific findings and massive efforts to integrate this information in the presence of an overwhelmingly skeptical and often hostile and certainly data censored/brainwashed scientific, public health, medical, and regulatory agency communities. This time the science was sufficient and the strategy and tactics able to demonstrate the biological reality of hormesis, its generality, dose responses features, underlying mechanisms, vast practical applications, and superiority over the threshold and linear dose response models.

Acknowledgment EJC acknowledges longtime support from the US Air Force (AFOSR FA9550-13-1-0047) and ExxonMobil Foundation (S18200000000256). The views and conclusions contained herein are those of the author and should not be interpreted as necessarily representing policies or endorsement, either expressed or implied. Sponsors had no involvement in study design, collection, analysis, interpretation, writing and decision to and where to submit for publication consideration.

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Further Reading Calabrese, E.J. (Ed.), 1992. Biological effects of low level exposures to chemical and radiation. Lewis Publishers, Ann Arbor MI. Calabrese, E.J. (Ed.), 1994. Biological effects of low level exposures (BELLE). Dose-response relationships. Lewis Publishers, Boca Raton, FL.

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Calabrese, E.J., 2014. Dose-response: A fundamental concept in toxicology. In: Hayes, A.W., Kruger, C.L. (Eds.), Hayes’ principles and methods of toxicology, 6th edn. CRC Press, Boca Raton FL. Calabrese, E.J., 2018. The dose-response revolution: How hormesis became significant, an historical and personal reflection. In: Rattan, S.I.S., Kyriazis, M. (Eds.), The science of hormesis in health and longevity, 1st edn. Academic Press, London.

Hiserodt, E., 2005. Under-exposed: What if radiation is actually good for you? Laissez Faire Books, Little Rock, AR. Mattson, M.P., Calabrese, E.J. (Eds.), 2010. Hormesis: A revolution in biology, toxicology and medicine. Humana Press/Springer, New York.

Rattan, S.I.S., 2014. In: LeBourg, E. (Ed.), Hormesis in health and disease. CRC Press, Boca Raton, FL. Sanders, C.L., 2014. Radiation Hormesis and the linear-no-threshold assumption. Springer Publisher, New York.

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