TALES OF TWO SIMILAR
HYPOTHESES:
THE RISE AND FALL OF CHEMICAL
AND RADIATION HORMESIS
Edward J. Calabrese1 and Linda A. Baldwin
Department of Environmental Health Sciences
School of Public Health
N344 Morrill Science Center
University of Massachusetts
Amherst, MA 01003
Tel: 413-545-3164
Fax: 413-545-4692
Email: edwardc@schoolph.umass.edu
1 To whom correspondence should be sent
ABSTRACT
This paper compares the historical developments of chemical and radiation hormesis from their respective inceptions in the late 1880's for chemical hormesis and early 1900's for radiation hormesis to the mid 1930's to 1940 during which both hypotheses rose to some prominence but then became marginalized within the scientific community. This analysis documents that there were marked differences in their respective temporal developments, and the direction and maturity of research. In general, the formulation of the chemical hormesis hypothesis displayed an earlier, more-extensive and more sophisticated development than the radiation hormesis hypothesis. It was able to attract prestigious researchers with international reputations from leading institutions, to be the subject of numerous dissertations, to have its findings published in leading journals, and to have its concepts incorporated into leading microbiological texts. While both areas became the object of criticism from leading scientists, the intensity of the challenge was greatest for chemical hormesis due to its more visible association with the medical practice of homeopathy. Despite the presence of legitimate and flawed criticism, the most significant limitations of both chemical and radiation hormesis and their respective ultimate undoing were due to their: (1) lack of development of a coherent dose-response theory using data of low dose stimulation from both the chemical and radiation domains; (2) difficulty in replication of low dose stimulatory responses without an adequate study design especially with respect to an appropriate number and properly spaced doses below the toxic threshold; (3) modest degree of stimulation even under optimal conditions which was difficult to distinguish from normal variation; and (4) lack of appreciation of the practical and/or commercial applications of the concepts of low dose stimulation.
Keywords: hormesis, low dose, stimulation, -ß-curve, radiation, biphasic, U-shaped, risk assessment
INTRODUCTION
We have recently assessed the early history of chemical1 and radiation2 hormesis and factors contributing to their respective marginalization within the scientific community.3,4 As a result of these assessments it became clear that chemical and radiation hormesis displayed an historical development quite distinct from each other with respect to temporal development, scientific maturity and sophistication, animal and plant models studied, type and motivation of scientific opposition, and consideration for commercial application. It should be noted that the term hormesis was proposed in 1943 by Southam and Erhlich5 who observed that chemical extracts of cedar stimulated fungal growth at low doses, but inhibited at higher doses. The authors were apparently unaware of the fact that this phenomenon was previously characterized as either the Arndt-Schulz Law or Hueppe's Rule. This paper will use the term hormesis to describe the low dose stimulatory phenomenon but is cognizant that this term was created after the early historical development and scientific marginalization of both chemical and radiation low dose stimulation (e.g., Arndt-Schulz Law) hypotheses.
The present paper will extend these previous efforts by directly comparing both chemical and radiation hormesis with respect to their scientific development and research directions, the quality of their developmental maturity, and generalizability of their two hypotheses, as well as their respective underlying weaknesses which led to the demise of each hypothesis.
CHEMICAL HORMESIS DEVELOPS EARLIER THAN RADIATION HORMESIS
The concept of low dose chemical stimulation had its origins in the later decades of the 19th century. The predominant direction in these early years concerned the effects of various chemical agents on plant and fungal growth (Table 1). In fact, prior to 1900, the general belief had emerged in the realm of chemical toxicology that low doses as a general rule had the capacity to stimulate, while higher doses would inhibit the activity. This so-called truism became referred to as either the Arndt-Schulz Law or Hueppe's Rule as a result of Hugo Schulz's research on chemical stimulation of yeast metabolism51,90,91 and Ferdinand Hueppe's research on chemical stimulation of bacterial growth.78
Table 1: Early historical references for low dose stimulatory response by chemicals.
The concept of radiation hormesis followed that of chemical hormesis and of course had to await the discovery of X-rays in 1895 by Roentgen, uranium by Becquerel in 1896 and radium by the Curies in 1898. However, the biological effects of ultraviolet (UV) radiation was actively researched much earlier with the report of Downs and Blount92 being credited with the discovery of the killing action of sunlight on bacteria and other microorganisms, thereby drawing attention to the importance of chemically active spectral radiation. By the 1890's it was clear that UV light was an important factor, if not the principal factor, in the reported lethal effects of sunlight. By the early years of the 20th century, the region of lethal actions had been considerably refined to progressively more specific UV wavelengths93 (Table 2).
Table 2: Early historical references for low dose stimulatory response by radiation.
Thus, it was quite clear that evaluation of the concept of low dose chemical stimulation had a strong headstart over its radiation counterpart. This differential advance in favor of chemical hormesis can be seen not only in the sheer volume of published research activity, but also in what was studied (Figure 1). In general, the most active early areas of low dose chemical stimulation research was that of plant growth, followed by fungal growth and metabolism, with bacterial metabolism a distant third (Table 1, Figure 1). By the end of the 19th century, there had been considerable activity in these two dominant areas principally driven by hopes of industrial and/or agricultural applications. In the case of plant research, there was the obvious interest in the enhancement of agricultural productivity, while in the case of fungal growth and metabolism there was great interest in finding ways to enhance, refine, and apply the process of fermentation.
In the case of plant growth a separate line of research developed in the late 1890's by Kahlenberg and his associates at the University of Wisconsin39-41 who were more concerned with the assessment of the biological effects of highly dilute solutions based principally on the application of newly developed concepts of physical chemistry permitting the use of molar solutions rather than percentages as had been the case
In the case of chemical stimulation of plant growth, the first decade of the 20th century witnessed the transformation of relatively naïve experimental designs into an impressive formulation of concepts that established a strong foundation for low dose chemical research. Most notably during the first decade of the 20th century were the contributions of True and Gies,42 Cameron and Breazeale,43 True and Oglevee,44 Jensen,45 and Schreiner and Reed.34 These investigators incorporated the concept of large numbers of doses, doses below toxic thresholds, and high sample sizes along with the concurrent measurement of multiple endpoints. In addition, these authors began to display these data on highly illustrative graphs enhancing presentation of the data and conceptual understanding.
During the late 1890's initial hypotheses were formulated concerning the underlying mechanism of the low dose response and the role of such mechanisms in the organism's metabolism. For example, Townsend15 first proposed that low dose chemical stimulation was an overcompensation for chemically induced injury, an observation that was subsequently supported and generalized to other models during these early years of development.132,133 In fact, this initial concept of Townsend15 remains the dominant conceptual explanation of the low dose stimulatory phenomenon.134 In addition, Richards55,56 proposed the concept of enhancement of metabolic economic efficiency as a result of exposure to low levels of chemical stress. While these conceptual frameworks were being developed and debated, True and Oglevee44 developed the first graphing of the so-called hormetic -ß-curve with respect to dose stimulatory range, maximum stimulatory response, and relationship of the maximum stimulatory response to the toxic threshold which were remarkably similar to more modern representations.135,136 All of these developments occurred well before the genuine onset of low dose stimulatory research in the radiation domain.
The course of low dose radiation research displayed both similar and different research tracts than that for the chemical hormesis research. The most significant area of similarity was the interest in the effects of X-rays and radium on plant growth. The quality of the study designs with respect to low dose radiation stimulation of plant growth did not reflect the rapidly developing maturity of the chemical hormesis researchers. For example, by 1900 the area of low dose chemical stimulation was well on its way to having adopted modern study design criteria, whereas the early researchers in the area of radiation hormesis often displayed noticeable deficits in study design. This was clearly illustrated in the publication of Gager94 who often employed in his over 90 experiments inadequate sample size, inadequate reporting of experimental methods and overinterpretation of preliminary findings. However, this differential maturity seen in the design, conduct, and interpretation of early low dose stimulation studies appeared to be related to the fact that the first wave of chemical researchers in the U.S., such as True, Jensen, and Stevens, were part of the broader and well established plant/agricultural research community with considerable laboratory and field research experience. In addition, there was a strong tendency to publish in the most well established journals of that era, such as the Botanical Gazette, which further insured a more advanced professional product.
Part of the differential quality of the earlier investigations on radiation effects on plant growth was the difficulty in establishing a quantifiable radiation dose metric. When this became established by the early 1920's it encouraged researchers in the plant area to collaborate more effectively with persons trained in radiation dosimetry. For example, the 1931 study by Failla and Henshaw137 represents an excellent collaboration between radiation dosimetry experise (Failla) and plant biology (Henshaw). However, this challenge of bringing together such initially divergent expertise resulted in the differential rate of maturity between the chemical and radiation domains.
In addition to the above mentioned factors affecting the limitations in study design, it was also influenced by both the object of exposure and technological developments. That is, the generally lower sample size among early plant radiation researchers was influenced by the fact that exposure was usually administered to seeds rather than the seedling or later developing plant and the fact that the X-ray Coolidge tube was of limited size and could only accommodate a fixed number of seeds.138 This also affected studies with larger seeds more differentially. While it would have appeared that such a technological limitation should not have been an issue, it nonetheless affected the sample size of numerous earlier plant studies. The area of chemical plant research did not have such constraints.
Of particular note is that the first American researchers assessing potential low dose stimulatory effects of X-rays on plant growth were at the University of Chicago in the late 1920's, 139,140 some 30 years after the discovery of X-rays! The reasons for this late application to plant growth of low doses of X-rays in the U.S. are unknown, given its widespread use in the plant domain in other countries including various European countries and Japan and the earlier assessment and claims of radium induced plant growth stimulation in the U.S.2
Perhaps the most aggressive area of research in low dose radiation was in the area of medical applications for the treatment of various diseases. While X-rays were being used to treat tumors within a year of their discovery, it took about ten years for the concept to emerge that certain "low" doses of X-rays (i.e., about 10-50% of the human erythema dose, 60-300 R) to treat a wide spectrum of human inflammatory diseases.141-145 This concept of employing radiation at relatively low doses for therapeutic purposes never developed in an analogous fashion in the area of chemical stimulation except in so far as the Arndt-Schulz Law became a theoretical framework to support the medical practice of homeopathy. However, in the case of radiation the low dose X-ray treatment was part of the traditional medical establishment with publications and advances in this area in such journals as the Journal of the American Medical Association, the New England Journal of Medicine, Radiology, and others. Thus, in contrast to the relationship of chemical hormesis to the fringe medical practice of homeopathy low dose radiation therapy was part of the traditional medical establishment.
Other notable developments included the later and active research of UV on fungi in the 1920's and 1930's. (Table 2). In fact, it was during this research that the first conceptual development of hormetic mechanisms was presented by radiation hormesis researchers. That is, Smith125 reported that UV-induced mycelium growth occurred only after an initial injury. This concept was quite similar to that reported almost 40 years before by Townsend.15
SIMILARITIES AND DIFFERENCES IN THE OBJECTS OF STUDY IN CHEMICAL AND RADIATION HORMESIS
A marked difference between the chemical and radiation low dose stimulatory response was the near total absence of such observations with radiation on bacteria, but the striking productivity of this area in the chemical domain in the 1920's and 1930's (Tables 1 and 2) particularly at Yale University where a long series of Ph.D. students under the highly respected Professor Winslow clearly established the reproducible nature of the hormetic response. Of particular note was the research of Hotchkiss89 who assessed the effects of twenty-three chemical agents on bacterial growth, with fifteen demonstrating low dose stimulatory effects. The work of Hotchkiss89 was remarkable for its strong study design features, large number of doses especially below the toxic threshold, and consistent nature of the low dose stimulatory response. In fact, these and the related findings of Winslow's other students became incorporated into leading microbiological texts of the mid 20th century146-148 along with incorporation of standard assays in laboratory exercises for introductory college students.149
A general area that was pursued by those involved in radiation but not chemical hormetic research was the area of cell division. This is seen in research concerning cell division in paramecia, the chick embryo, and various cell types. This research became more substantial in the 1920's with the generally consistent conclusion that low doses of X-rays can stimulate cell division in a variety of models.
The role of low dose stimulatory responses generally did not address the issue of longevity during the early years of the 20th century. However, two excellent papers were provided by Davey of General Electric in which he unexpectedly reported a low dose of X-rays enhanced longevity in the confused flour beetle.128 These findings were confirmed and extended in a follow-up paper by the same author.129 No comparable paper was presented on the chemical side. However, even more surprising is that the striking findings of Davey128,129 were not followed up for some forty years until Cork150 confirmed the life extending response with a gamma ray source using the same animal model.
In summary, the development of research in the area of chemical hormesis occurred earlier, was more extensive, and considerably more mature with respect to the quality of study design and conceptual understanding of a mechanistic framework. However, the two areas are similar in that both were influenced in their early development by commercial applications.
With respect to commercial applications the most visible and high stakes activities were concentrated within the area of radiation hormesis. In these cases a number of attempts explored the use of radionuclides to enhance plant growth. By 1923 a patent was issued on a process to cause radiation induced stimulation of plant growth.151 A number of commercial businesses were created for this purpose but with little tangible and no long lasting success.96,152 Factors affecting the lack of apparent commercial success were complex, involving technological, biological, social, and economic factors. From the biological perspective, the "fact" of stimulation was assumed to have been proven before reasonably convincing data had been established. In addition, there was little appreciation at that time (i.e., 1915-1930) concerning the nature of low dose stimulation dose-response relationship, including the recognition that the average maximum increase would only be 30-60% above controls and that each plant species and perhaps each set of experimental conditions could display a different optimal dose. Such complexity especially in a new developing area clearly provided the basis for failure for commercial success. In addition, the cost of radium for potential use as fertilizer was quite high, being about $100,000/gram in 1915.99 In order to double the background levels of radium emanation (radon) in the soil, Ramsey100 estimated one must use 75 milligrams/acre (i.e., $7500/acre).
The area of low dose clinical treatment with X-rays had a long term series of successes that were adequately documented in highly prestigious journals.141-145 However, X-ray treatment, like other treatments, competed as a therapeutic option with other available treatments and/or procedures. In the case of X-ray treatment of inflammatory diseases, it eventually lost out to advances in chemotherapeutics which was reinforced with a growing concern over potentially harmful effects of X-rays even at low doses.
WHY RADIATION AND CHEMICAL HORMESIS WERE REJECTED
The rejecting of chemical and radiation hormesis hypotheses has some general overlapping features but a number of distinctive aspects as well. First, while this discussion has divided the debate into chemical and radiation hormesis, it is not clear that either one of these areas were identified as a stand alone "field". In the case of chemical hormesis it was uncommon for plant chemical hormesis researchers to cite those in other chemical areas such as fungi and bacteria. Furthermore, the chemical and radiation hormesis researchers generally never cited each other. In addition, there was a dearth of review papers on the topic of low dose stimulatory responses. This lead to only a very limited summarization of relevant papers in either the introduction or discussion of focused research reports. While this intellectual truncation is appropriate for narrow research papers, the general lack of critical broad reviews of the literature limited the capacity to develop more integrated assessments of the broad scientific literature. While the publication of critical and integrated reviews is common today, in the early decades of the 20th century it was not common. In fact, it is ironic that the first major review of the literature on radiation hormesis was of a highly critical nature (Johnson153 see below). This lack of broad integration coupled with the absence of a central dose-response concept resulted in a poorly developed general understanding of hormetic dose-response relationships. Thus, low dose stimulatory findings were quite truncated into very narrow model (e.g., plant, bacteria, etc.) specific responses with little attempt to develop a general focus on dose-response relationships. Such a lack of an integrated focus on the hormetic dose-response was a fundamental underlying factor that contributed to the inability of these hypotheses to better establish themselves.
Radiation hormesis, with a more limited database to support its premise than chemical hormesis, became the object of a highly successful attack by Edna Johnson in the 1930's.153,154 Of particular significance was that the Johnson criticism targeted the strongest experimental basis of radiation hormesis, that is, the effects of X-rays on plant growth. As noted above, the review of Johnson153 was not only one of the first major reviews of the literature on the effects of X-rays on plant growth it also received additional prestige for being part of a major National Research Council (NRC) assessment of the biological effects of radiation. This combination proved to have considerably greater impact than criticism tucked away in a discussion section of a focused research paper. With the X-ray/plant component of the radiation hormesis perspective placed on weakened grounds by the review of Johnson,153 there was little countervailing opposition to offset the criticism or limit its impact. More specifically, there was no corresponding supportive evidence with bacteria, and only limited supportive evidence with fungi (Table 2). The only other potential widespread strength supporting the concept of low dose stimulation was in the area of medical treatment and this itself was on weak grounds due to overzealous claims for beneficial radiation exposure (e.g., mild radium therapy)155 and growing fears of low dose mutational and cancerous effects of X-rays.156
The demise of radiation hormesis is understandable especially in light of its limited database, difficult findings to reproduce, harsh criticism from leading scientists coupled with a growing fear of radiation and an emphasis on defining safety standards that required defining frankly toxic effect levels, lowest adverse effect levels and toxic thresholds. These became the predominant questions in the mid 1930's, not whether low doses cause a marginal, hard to reproduce and even harder to interpret stimulatory response. Once radiation hormesis was pushed aside and not considered credible, funding became generally unavailable and it became further marginalized.
The chemical hormesis area should have survived as a central hypothesis not only as a result of its better general database but also because it had direct linkage with numerous well known scientists or their students such as Louis Pasteur [Raulin's work50 in Pasteur's laboratory], Robert Koch [Ferdinand Hueppe78 was a protégé of Koch], Wilhelm Ostwald [Kahlenberg (see Kahlenberg and True; 39 Copeland and Kahlenberg41) received his Ph.D. with Ostwald in Germany before returning to the University of Wisconsin], Charles Richet157,158 (the Nobel laureate for discovering anaphylaxis) who demonstrated low dose stimulatory effects in fermentation systems, and a strong series of U.S. academics at prestigious institutions (i.e., Duggar at the University of Wisconsin, Townsend and Richards at Columbia University, Stevens at the University of Chicago and later at Stanford University, Winslow at Yale University) and True with the U.S. Agricultural Research Service after moving from the University of Wisconsin. No comparable grouping of outstanding researchers with such powerful lineages and/or institutions and strong publication records were present with radiation hormesis. Yet despite the greater historical foundations, stronger data, acceptance as a central concept in bacteriology and long listings of prestigious scientists supporting it, all factors less developed in radiation hormesis, both chemical and radiation met the same fate of marginalization about the same time.
Despite the above outstanding research and academic pedigree of hormesis researchers of the early decades of the 20th century, the area of low dose chemical stimulation was to become the object of intense criticism by the next generation of dominant figures in the field of pharmacology and toxicology. This criticism was to have its origin in the fact that this area of research was too closely allied with the controversial medical practice of homeopathy.1 The area of chemical hormesis had become used as an explanatory factor by advocates of the medical practice of homeopathy. In fact, Hugo Schulz, the microbiologist who first reported that low doses of numerous chemicals stimulated yeast metabolism, joined with Rudolph Arndt (the homeopathic physician) and together promoted the broad generalizability of the low dose stimulatory curve into a prime explanatory framework of how homeopathic drugs worked. This close association of a scientific hypothesis with a politicized medical practice was criticized as early as 1896 by Hueppe.78 Nonetheless, the association of hormesis to homeopathy remains even to the present.159 However, in 1937 the prestigious pharmacologist A.J. Clark of the University of Edinborough published his classic text, "Handbook of Pharmacology", in which he devoted 15% to a refutation of the Arndt-Schulz Law.160 Clark, the discoverer of the first molecular receptor (i.e., the acetylcholine receptor), was a towering scientific feature by himself, but he also had an unusually strong collaboration with several of the most powerful and respected biostatisticians of that era.
At this time, the fundamental nature of the dose-response was powerfully articulated and was greatly affected by the very biostatisticians (e.g., Bliss, Trevan) who worked with Clark. Lacking any comparable countervailing intellectual force at the time, the concept of hormesis, especially chemical hormesis, became a cultural victim of guilt by association with homeopathy. This marginalization was encouraged by traditional medical philosophy because of the long standing antipathy with homeopathy. Since pharmacology and toxicology developed most extensively within traditional medical schools, it was only natural to have physician-trained pharmacologists/toxicologists lump hormesis with homeopathy and the marginalization was complete.
This paper has argued that the concepts of chemical and radiation hormesis had remarkably independent histories with respect to temporal development, direction of research, selection of experimental model, quantity and quality of supportive data, acceptance by the broader scientific community and commercial applications. While it may be the case that the entire fields of chemical and radiation hormesis are perceived as simply one concept, the actual unfolding of these two areas of research has been quite distinct. The separate developments of chemical and radiation hormesis which are seen at the start of the 20th century has been maintained to the present time. Thus, even today there is very little cross communication between those working in the areas of radiation and chemical hormesis.
Even in their respective demises there was also considerable uniqueness (Table 3). That is, the area of chemical hormesis was plagued by its long standing and close association with the medical practice of homeopathy which set the stage for a guilt by association response from traditional medicine which was strongly influencing textbook development, professional society activities and funding programs. In contrast, radiation hormesis was plagued by the high dose applications of radiation which dominated medical practices and made many ill, and the overzealous claims of radium profiteers with the highly visible and tragic death of the millionaire industrialist and playboy Eben M. Byers, which resulted in the end of the era of mild radium therapy.155
Table 3: Comparison of factors leading to the demise of chemical and radiation hormesis.
Both areas of hormesis were also plagued by different but highly visible critics. In the case of chemical hormesis the attack was profoundly more intense, intentional, and systematic. As noted above, the allocation of 15% of what has been referred to as a major and classic text for the repudiation of the Arndt-Schulz Law by A.J. Clark was the type of challenge that radiation hormesis did not experience. Radiation hormesis certainly had its critics, such as Johnson,153 but they were more generally limited and focused within the narrower context of a particular research paper. The use of low dose radiation to treat human inflammatory diseases became widely integrated within modern medical practice from the early 1900's through the 1940's. While these practices were not generally referred to as being related to the Arndt-Schulz Law, there is little question that its advocates such as Desjardin, chief of radiology at the Mayo Clinic, clearly articulated the view that low doses were beneficial for the patients' conditions while higher doses were progressively less effective and even higher doses harmful. The low dose X-ray therapy which typically utilized only a single exposure was simply out-competed by novel therapies of the mid 1940's such as the progression of antibiotics which brought rapid cures without the residual fears of adverse effects of radiation treatment.
Despite dissimilarities in both chemical and radiation hormesis, the most serious challenges were ones they held in common (Table 3). That is the basic reality that hormesis affected a modest stimulatory response over a limited range of doses. It also requires very stringent study design criteria and endpoint selection in order to properly assess it. These factors affected both its reproducibility and its commercial applications and in the end these most fundamental factors are the principal determining factors for their common demise.
ACKNOWLEDGMENT
This work was sponsored in part by a grant to the University of Massachusetts (Edward J. Calabrese, Prinicple Investigator) by the U.S. Nuclear Regulatory Commission.
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