Hormesis: Difference between revisions

Latest revision as of 06:01, 29 August 2024

Main Article

Discussion

Introduction

Alle Ding sind Gift, und nichts ohn Gift; allein die Dosis macht, dafβ ein Ding kein Gift ist.

All things are poison and nothing is without poison, only the dose permits something not to be poisonous.

—Paracelsus (Philip von Hohenheim) (1493-1541) ^[4]

Medicine or poison? Depends on dose

The fundamental characteristic of hormesis is its 'non-monotonic' or 'biphasic' feature, meaning the response to the agent in question adapts the organism to subsequent or higher doses, or changes direction with increasing doses. In respect of the latter, the low dose-range where a stimulation occurs — stimulatory zone — may have either beneficial or detrimental effect to the organism, though interest often concentrates on instances in which the low-dose effect confers benefit, the higher doses detriment. 'Stimulation' thus may refer to stimulation of benefit or detriment.

"Poisons that injure or kill at high doses can have the opposite effect at low doses, [Professor Calabrese] says, and the paradox holds true for every conceivable measure of health—growth, fertility, life span, and immune and mental function. The effect is known as hormesis, from the Greek word for excite. "The implications," [Professor Calabrese] says, "are enormous."" (Hively, 2002, speaking of biphasic effects of radiation exposure)^[5]

Biologists often begin their description of hormesis with the aphorism that 'what doesn’t kill you makes you stronger' — implying an 'adaptation' response — or the aphorism that 'what makes something a medicine or a poison depends on dose'. The first aphorism implies the existence of agents or events potentially causing harm, but if insufficient to do so under the circumstances prevailing, actually confer benefit. The second aphorism emphasizes the dichotomous effects of the dose of a so-called medicine. The quantifiable, in-principle, biological phenomenon of ‘hormesis’ manifests itself in those ways.

In their 2008 New Scientist article "Best in Small Doses", hormesiologists Mark Mattson and Edward Calabrese write this applicable to the aphorism about adaptation:

"It describes the theory of hormesis - a process whereby organisms exposed to low levels of stress or toxins become more resistant to tougher challenges."^[6]

[New Scientist editors announce the article as "When a little poison is good for you".]

Hormesis manifests itself not only in the circumstance of exposure to potentially toxic chemicals. Any exposure or event that tends to stress the living system’s prevailing physiological status can potentially elicit a hormetic non-monotonic response.^[1] "Examples include many chemicals, temperature, radiation, exercise, energy intake and others." ^[1] Increasing the amount of physical activity by a more-or-less sedentary person, while it constitutes a stress on the cardiovascular and neuromuscular system long accustomed to relatively modest demands, may benefit the person’s general state of health. But an overenthusiastic convert to exercise may perform too much too quickly, resulting in injuries of many different kinds.

What doesn't kill you makes you stronger

Mattson and Calabrese added another twist to hormesis when they it as "a process whereby organisms exposed to low levels of stress or toxin become more resistant to tougher challenges"^[6] [emphasis added (as underline)] They write of the manifold defense molecules that the body actuates when a threat appears, that calling them to duty, so to speak, both counters the actuating threat and increases the body's ability to resist other threats. They exemplify that with the nerve cell toxicity produced by the high levels of the neurotransmitter, glutamate, that brain injury may release into the synapses connecting nerve cells, but which at lower levels can beneficially affect nerve cell survival and growth. As another example of what they call "hormetic stressors", they write of the natural plant chemicals that act as 'natural' pesticides, protecting the plants against 'natural' pests. In the amounts of those so-called phytochemicals that we consume with our fruit and vegetables, they actuate our body's responses to stress, but in high enough doses can cause toxic injury.

Some biologists, including health science biologists, refer to an adaptive response of cells and organisms to 'stress' of various categories, adaptation characterized by stronger resistance to the stressor when previously exposed to it at low levels.^[7]

‘Hormetic’ dose-response effects appear as a general biological phenomenon among numerous animal species, non-gender- or age-specific, among microorganisms as well. The response parameters — the effects displaying hormetic biphasicity — include growth, longevity, metabolic phenomena, disease incidence, cognitive functions, and immune responses. Exercise, caloric restriction, ethanol, caffeine, and various other stress factors, including radiation exposure, can also deliver hormetic responses.^[6] ^[1] ^[8] ^[9] ^[10]

British hormesiologist A. R. D. Stebbing explains the hormetic effect as an evolved biological adaptation that prepares organisms to resist the toxic effects of a range of different environmental stressors,^[11] ^[12] comparable to the evolved biological adaptation referred to as 'homeostasis':

Ockham’s Razor leads one to look for the most economical hypothesis, which for hormesis is more likely to depend on some common property of the organisms than the toxic agents to which they are exposed. The range of examples suggests that hormesis is not so much an effect of the specific agents that induce it, but an adaptive response to the inhibitory effect they share, because it is improbable that any toxicant-specific interpretation could account for the widespread occurrence of the b[eta]-curve [the biphasic hormetic curve]. The idea that hormesis is due to a biological response is also attractive in an evolutionary sense, because organisms are thus pre-adapted to toxic inhibition whatever the specific cause.^[12]

At low doses of stressor, the evolved adaptive, or homeostatic, mechanism 'overcompensates', bringing about the stimulatory or beneficial effect, the 'overcompensation' feature itself an evolved adaptive mechanism that strengthens with exposure to the stressor, accounting for ....a process whereby organisms exposed to low levels of stress or toxins become more resistant to tougher challenges.^[6]

Proposed mechanisms for hormesis

Holding ref:^[13] ^[14] ^[15]

Controversial issues

The concept of hormesis has not escaped its share of controversy. Some researchers question whether scientists have developed adequate methods for distinguishing when a beneficial effect ends and a toxic one begins. The exact threshold for when a toxic reaction starts may vary by individual, making it difficult to use hormesis as a basis for drug therapies. Skepticism arises, too, when the basic concept is extended to ionizing radiation, such as x-rays, for which low doses have been shown to have beneficial effects on healthy lab animals. Various scientific advisory bodies, however, have rejected radiation as unsafe for humans even at the lowest levels.

— By Mark P. Mattson, Jun 16, 2015, Scientific American Magazine

Scientists have not universally accepted hormesis, though the discussion remains active. ^[16]

Thayer et al. write:^[17]

Cook and Calabrese (2006)^[18] make inaccurate claims about our perspective on hormesis (Thayer et al. 2005).^[19] They define hormesis as "low-dose stimulation and high-dose inhibition," declaring "beneficial/harmful effects should not be part of the definition, but reserved to subsequent evaluation. . . ." Yet, they advocate higher permissible environmental levels of hazardous agents based on purported health benefits. Cook and Calabrese promote changing the way carcinogens are regulated to accommodate hormesis, recognizing that this "would result in cancer risk assessment values about 100- to 200-fold higher than currently employed" (Calabrese and Cook 2005).^[20] Previously, Calabrese and Baldwin (2003a)^[21] stated, "agencies will need to accept the possibility (actually, the likelihood) that toxic substances, even the most highly toxic (e.g., cadmium, lead, mercury, dioxin, PCBs, etc.) can cause beneficial effects at low doses."

Subsequently, however, Calabrese, the leading explicator and articulator of the hormesis concept, clarifies his position, writing in 2008:

The hormetic dose–response may be reliably described as a being a stimulation in the low dose zone, followed by an inhibitory response at higher doses....the stimulatory zone [dose range where stimulation occurs] defines the therapeutic window. It may also define an adverse effect window, as in the case when low doses of anti-tumour drugs stimulate tumour growth [citation given]. It is also important to recognize that the hormetic stimulatory zone is graphically contiguous with the pharmacologic/toxicologic threshold. This indicates that there is the distinct possibility of a desired therapeutic dose being a toxic dose to some individuals due to extensive interindividual variation.^[9]

History of hormesis concept

Hormesiologist A.R.D. Stebbing offers a succinct account of the history of the phenomenon and concept of hormesis: ^[22] ^[23]

Examples of hormesis gathered from the literature show that hormesis has a long and interesting history. The concentration-response curves for quite a wide range of toxic agents followed a typical pattern, termed the betacurve (Townsend & Luckey, 1960). The occurrence of such curves in toxicological experiments was discovered independently and named on several occasions. Over a century ago Schultz's experiments (1888) showed that many chemical agents had the effect of stimulating the growth and respiration of yeast. The phenomenon became known as the Arndt-Schultz Law and was widely referred to in the pharmacological literature for over 30 years and became one of the scientific principles on which homeopathy is based. However, the potency of homeopathic medicines is believed to increase with their dilution over many orders of magnitude, rather than restricted to a narrow range of concentrations like hormesis.^[22]

Hueppe (1896) at about that time made similar observations on bacteria, apparently unaware of Schultz's experiments. His generalization became known as Hueppe's Rule.^[22]

Long before them both, the German alchemist and physician Theophrastus Bombastus von Hohenheim ((1493-1541), who coined for himself the name *Paracelsus*, had recognized with respect to the medical use of small amounts of toxic chemicals that their efficacy depended principally on the dose. Such ideas are perhaps more easily accepted nowadays, when it is in the experience of most to use the stimulatory effects of alcohol, caffeine or nicotine, all of which are toxic at high concentrations.^[22]

Much later Southam and Ehrlich (1943) studied the effect of a natural antibiotic in cedar wood that inhibits the growth of wood-decaying fungi. They found that subinhibitory concentrations of the antibiotic had the reverse effect and stimulated fungal growth. The term "hormesis" was coined to describe it; which we still use today. Some of the observations have an interesting origin. In the later stages of World War II, when supplies of penicillin were in such short supply, work of Miller et al. (1945) explained why reducing the dose to make short supplies of the new drug go further sometimes had the reverse of the desired effect. At low doses penicillin actually stimulated the growth of Staphylococcus . In other examples closer to my own field, experiments with oyster lar vae showed that low levels of many pesticides actually stimulated growth in the same way (Davis & Hidu, 1969). The greatest authority in the field of hormesis is Dr Thomas Luckey, whose early work was on the use of antibiotics as dietary supplements to stimulate growth in poultry (Luckey, 1956)^[22]

References cited by Professor Stebbing in the above excerpt:

Definitional considerations

Hormesiologists Edward J. Calabrese and Linda A. Baldwin provide an introduction to definitional considerations with the abstract of their paper, Defining Hormesis ^[31] upon which the nuances of the concept permit explication:

Much confusion surrounds the concept of hormesis and what its biological meaning represents. This paper provides a definition of hormesis that addresses its historical foundations, quantitative features, and underlying evolutionary- and toxicologically-based mechanistic strategies.

Hormesis should be considered an adaptive response characterized by biphasic dose responses of generally similar quantitative features with respect to amplitude and range of the stimulatory response that are either directly induced or the result of compensatory biological processes following an initial disruption in homeostasis.

Given the limited magnitude of the stimulatory response (i.e., usually 30-60% greater than controls at maximum), heightened study design and replication requirements are often necessary to ensure reliable judgments on causality. Even though hormesis is considered an adaptive response, the issue of beneficial/ harmful effects should not be part of the definition of hormesis, but reserved to a subsequent evaluation of the biological and ecological context of the response.^[31]

More recently, Vaiserman writes:

Hormesis (the shape of the dose–response patterns when low doses elicit an adaptive response of the cell/organism...^[32]

Mitochondrial hormesis (mitohormesis)

Holding refs:

^[33]

^[34]

Hormesis and plant biology

Numerous studies indicate that plants exhibit hormetic dose-response effects to cytotoxic stressors quantitatively similar to those occurring in animals.^[35] Plant biologists study how hormesis in plants might be exploited for plant growth enhancement and for soil remediation.^[35]

Xenohormesis

Xenohormesis, a subdiscipline of hormesis, refers to the phenomenon of adaptive cellular responses of humans and other mammals to the typically low-dose amounts of plant toxins consumed with their ordinary diets — adaptive responses that confer resistance to stressors and other benefits to health.^[36] ^[37]

Plants produce toxins, called phytoalexins, that protect them from environmental stressors, including a variety of injurious organisms, for example insects. The low-doses that humans receive from consuming plant foods serve as mild stressors, which the body uses to a health advantage.

What doesn’t kill you makes you stronger. Dose determines whether a substance acts as a poison or a tonic.

Ames and colleagues report:

We calculate that 99.99% (by weight) of the pesticides in the American diet are chemicals that plants produce to defend themselves. Only 52 natural pesticides have been tested in high-dose animal cancer tests, and about half (27) are rodent carcinogens; these 27 are shown to be present in many common foods. We conclude that natural and synthetic chemicals are equally likely to be positive in animal cancer tests. We also conclude that at the low doses of most human exposures the comparative hazards of synthetic pesticide residues are insignificant. ^[38]

If low-dose intermittent consumption of chemicals that induce cancer at high-dose behave hormetically, the word “insignificant” in the quote understates the case.

Xenohormesis more broadly refers to the adaptive responses to the sensing, from other species, of chemical clues about potential environmental dangers, an evolved preconditioning function, predicting the future, serving survival advantage given the inevitable inimical influences in Earth’s bio- and geospheres.^[37]

Hormesis vs. homeopathy

Menachem Oberbaum, Noah Samuels, and Shepherd Roee Singer, of The Center for Integrative Complementary Medicine, Shaare Zedek Medical Center, Jerusalem, Israel, argue that "hormesis is not homeopathy", stating, among other differences, that:

Whereas hormetic (chemical) responses are induced by small but measurable concentrations (above Avogardo’s number), homeopathic concentrations are often far below this. The use of a remedy with a "concentration" of 10^-400 of the stem solution is common practice in classic homeopathy....Hormetic substances do not require any special preparation. Homeopathic remedies, in contrast, require a lengthy and exacting process before they are ready for administration.^[39]

References and notes cited in text as superscripts

Many citations to articles listed below include links to full-text — in font-color blue. Accessing full-text may require personal or institutional subscription to the source. Nevertheless, many sources do offer free full-text, and if not, usually offer text or links that show the abstracts of the articles. Links to books variously may open to full-text, or to the publishers' description of the book with or without downloadable selected chapters, reviews, and table of contents. Books with links to Google Books often offer extensive previews of the books' text.

↑ ^1.0 ^1.1 ^1.2 ^1.3 ^1.4
Mattson M (2008) Hormesis defined. Ageing Res.Rev. 7:1-7 PMID 18162444.
- Abstract: Hormesis is a term used by toxicologists to refer to a biphasic dose-response to an environmental agent characterized by a low dose stimulation or beneficial effect and a high dose inhibitory or toxic effect. In biology and medicine, hormesis is defined as an adaptive response of cells and organisms to a moderate (usually intermittent) stress. Examples include ischemic preconditioning, exercise, dietary energy restriction and exposures to low doses of certain phytochemicals. Recent findings have elucidated the cellular signaling pathways and molecular mechanisms that mediate hormetic responses which typically involve enzymes such as kinases and deacetylases, and transcription factors such as Nrf-2 and NF-kappaB. As a result, cells increase their production of cytoprotective and restorative proteins including growth factors, phase 2 and antioxidant enzymes, and protein chaperones. A better understanding of hormesis mechanisms at the cellular and molecular levels is leading to and to novel approaches for the prevention and treatment of many different diseases.
↑ Johnson MD.(2010) Human Biology: Concepts and Current Issues 6th ed. Boston: Benjamin Cummings. ISBN 978-0-321-70167-1.
↑ Olsen CM. (2011) Natural rewards, neuroplasticity, and non-drug addictions. 'Neuropharmacology 61:1109-1122.
↑ Chadwick W, Maudsley S. (2010) The Devil Is in the Dose: Complexity of Receptor Systems and Responses. In: Mark P. Mattson and Edward J. Calabrese, editors. Hormesis: A Revolution in Biology, Toxicology and Medicine. Springer. ISBN 978-1-60761-494-4.
↑ Hively W (2002) Is Radiation Good For You? Discover Dec. 1.
↑ ^6.0 ^6.1 ^6.2 ^6.3
Mattson M, Calabrese E (2008) When a little poison is good for you. New Scientist 9 August 2008. pp. 34-39.
- From the article: In 2008, Mark Mattson was chief of the laboratory of Neurosciences at the US National Institute on Aging and a professor of neurosciences at John Hopkins University in Baltimore, Maryland. He was then the most highly cited neuroscientist in the world. Edward Calabrese was a professor of toxicology at the University of Massachusetts in Amherst.
↑
Crawford DR, Davies KJA (1994) Adaptive Response and Oxidative Stress. Environ Health Perspect 102(Suppl 10) :25-28.
- Abstract:The ability of a cell, tissue, or organism to better resist stress damage by prior exposure to a lesser amount of stress is known as adaptive response. It is observed in all organisms in response to a number of different cytotoxic agents. One of these agents, oxidative stress, is known to induce an adaptive response in bacteria that is accompanied by the induction of many proteins. De novo protein synthesis is required for adaptive response to oxidative and other types of stress, indicating that newly synthesized protective proteins are necessary for adaptation. Adaptive response to oxidative stress also has been observed in mammalian cells. Several studies suggest it is necessary to first preexpose mammalian cells to a somewhat toxic oxidative stress in order to observe significant resistance to a subsequent highly lethal dose of oxidant. Cross-resistance of oxidatively stressed cells to other toxic agents including - and X-irradiation, heat shock, aldehydes, heavy metals, MNNG, N-ethylmaleimide, and heme also has been reported. Understanding oxidant adaptive response in more detail and identifying the protective proteins involved may prove to be of clinical benefit.
↑
Calabrese EJ, Blain R (2005) [http://dx.doi.org/10.1016/j.taap.2004.06.023 The occurrence of hormetic dose responses in the toxicological literature, the hormesis database: an overview. Toxicol. Appl. Pharmacol. 202:289-301 PMID 15667834.
- Abstract: A relational retrieval database has been developed compiling toxicological studies assessing the occurrence of hormetic dose responses and their quantitative characteristics. This database permits an evaluation of these studies over numerous parameters, including study design and dose-response features and physical/chemical properties of the agents. The database contains approximately 5600 dose-response relationships satisfying evaluative criteria for hormesis across over approximately 900 agents from a broadly diversified spectrum of chemical classes and physical agents. The assessment reveals that hormetic dose-response relationships occur in males and females of numerous animal models in all principal age groups as well as across species displaying a broad range of differential susceptibilities to toxic agents. The biological models are extensive, including plants, viruses, bacteria, fungi, insects, fish, birds, rodents, and primates, including humans. The spectrum of endpoints displaying hormetic dose responses is also broad being inclusive of growth, longevity, numerous metabolic parameters, disease incidences (including cancer), various performance endpoints such as cognitive functions, immune responses among others. Quantitative features of the hormetic dose response reveal that the vast majority of cases display a maximum stimulatory response less than two-fold greater than the control while the width of the stimulatory response is typically less than 100-fold in dose range immediately contiguous with the toxicological NO(A)EL. The database also contains a quantitative evaluation component that differentiates among the various dose responses concerning the strength of the evidence supporting a hormetic conclusion based on study design features, magnitude of the stimulatory response, statistical significance, and reproducibility of findings.
↑ ^9.0 ^9.1
Calabrese EJ (2008) Hormesis and medicine. Br J Clin Pharmacol PMID 18662293.
- Abstract: Evidence is presented which supports the conclusion that the hormetic dose-response model is the most common and fundamental in the biological and biomedical sciences, being highly generalizable across biological model, endpoint measured and chemical class and physical agent. The paper provides a broad spectrum of applications of the hormesis concept for clinical medicine including anxiety, seizure, memory, stroke, cancer chemotherapy, dermatological processes such as hair growth, osteoporosis, ocular diseases, including retinal detachment, statin effects on cardiovascular function and tumour development, benign prostate enlargement, male sexual behaviours/dysfunctions, and prion diseases.
↑
Stumpf WE (2006) The dose makes the medicine. Drug Discov Today 11:550-5 PMID 16713907.
- Abstract: Dose and time considerations in the development and use of a drug are important for assessing actions and side effects, as well as predictions of safety and toxicity. This article deals with epistemological aspects of dose selection by probing into the linguistic and cultural roots for the measure of medicine mediated by the medical doctor. Because toxicity is related to dose, historic and recent views suggest that less can be more. At low, medium and high dose levels, effects can differ not only quantitatively but also qualitatively. Dose-related target activation and recognition of enantiodromic thresholds between beneficial and toxic effects require elucidation of underlying events. Such studies, including hormesis and microdosing, call for extended ADME procedures with high-resolution methods in addition to the current low-resolution approaches. Improved information of drug logistics and target pharmacokinetics enables effective drug selection, dose determination and prediction. It also allows considerations of systems biology [i.e. integral (gestalt) pharmacology] exemplified by the drug homunculus, as in the case of vitamin D, that might lead to new paradigms and drug design.
↑
Stebbing AR. (1987) Growth hormesis: a by-product of control. Health Phys 52:543-7
- Abstract: Data from experiments, in which colonies of a hydroid, Laomedea flexuosa, were exposed to a range of Cu2+ concentrations and a marine yeast, Rhodotorula rubra, was exposed to a range of Cd2+ concentrations, not only exhibit hormesis, but also suggest how its occurrence in growth experiments might be explained. When growth data are considered as normalized specific rates against a time base, their oscillatory form indicates the output of a growth regulatory mechanism whose behaviour can be used to interpret the typical concentration-response curve exhibiting hormesis. Advantages may be conferred upon organisms whose growth control mechanisms overcorrect in response to low levels of inhibitory loading by toxic agents (stimulus), while at higher concentrations it is the overloading of such control mechanisms that results in the threshold in concentration-response curves (inhibition). It is suggested that if different examples of hormesis share a common explanation, it lies in the behaviour of homeostatic and homeorhetic feedback mechanisms, which respond to perturbation non-specifically and may overcorrect for adaptive reasons to low levels of inhibitory challenge.
↑ ^12.0 ^12.1
Stebbing AR. (2000) Hormesis: interpreting the beta-curve using control theory. J Appl Toxicol 20:93-101.
- Abstract: Data from experiments exposing colonial hydroids to toxic growth inhibitors have provided evidence of growth control mechanisms that respond adaptively to counter toxic inhibition. Analysis of growth data and the development of simulation models provide an interpretation of both alpha- and beta-curves. The hypothesis also suggests that hormesis is related to adaptation by growth control mechanisms that confer tolerance to subsequent exposure.
↑
Zhang Q, Pi J, Jarabek AM, Clewell III HJ, Anderson ME. (2008) Hormesis and adaptive cellular control systems. Dose-Response 6:196-208.
- Abstract: Hormetic dose response occurs for many endpoints associated with exposures of biological organisms to environmental stressors. Cell-based U- or inverted U-shaped responses may derive from common processes involved in activation of adaptive responses required to protect cells from stressful environments. These adaptive pathways extend the region of cellular homeostasis and are protective against ultimate cell, organ, and system toxicity. However, the activation of stress responses carries a significant energetic cost to the cell, leading to alterations of a variety of basal cellular functions in adapted or stressed cells. This tradeoff of resources between the unstressed and adapted states may lead to U-or inverted U-shaped dose response curves for some precursor endpoints. We examine this general hypothesis with chlorine, a prototype oxidative stressor, using a combination of cellular studies with gene expression analysis of response pathways and with computational modeling of activation of control networks. Discrete cellular states are expected as a function of exposure concentration and duration. These cellular states include normal functioning state, adaptive and stressed states at mild to intermediate exposures, and overt toxicity in the presence of an overwhelming concentration of stressors. These transitions can be used to refine default risk assessment practices that do not currently accommodate adaptive responses.
↑
Stebbing AR. (1998) A theory for growth hormesis. Mutat Res 403: 249-58. PMID 9726025.
- Excerpt: The hypothesis tested therefore was that hormesis is a consequence of an adaptive response common to biological systems to the inhibitory effect that the different agents have in common at higher concentrations.
↑
Calabrese EJ. (2001) Overcompensation stimulation: A mechanism for hormetic effects. Crit Rev Toxicol 31: 425-70.
- Abstract: Whether hormetic responses result from a direct or an overcompensation type of stimulatory response has been an unresolved and contentious issue in both radiation and chemical toxicology. The goal of the present article is to identify numerous examples of overcompensation stimulation in the biological/biomedical literature and to evaluate their descriptive and quantitative features. The findings provide support for the hypothesis that hormetic dose-response relationships from a broad array of biological models can occur after an initial disruption in homeostasis. The finding also demonstrates the significant role of temporal factors in the assessment of dose response relationships.
↑
LOW DOSE LINEARITY: THE RULE OR THE EXCEPTION. BELLE Newsletter Vol 6, No. 1, March 1997.
- From the Introduction: A recently published paper by Martha Crawford and Richard Wilson entitled "Low-Dose Linearity: The Rule or the Exception? " in the journal Human and Ecological Risk Assessment, Vol. 2, No. 2, 1996 argued that low dose linearity of the dose response curve might be the rule rather than the exception. While the assumption of low dose linearity has been widely accepted in concept and implemented in U.S. federal risk assessment practices for radiation and chemical carcinogens, it has not been believed to apply to non-carcinogens that have been accepted without controversy as having thresholds below which no adverse effects would be expected. However, Crawford and Wilson contend that the concept of low dose linearity is broadly generalizable and should apply to non-carcinogens as well. Their article, which urges a reconsideration of how background response is considered in risk assessment, challenges not only the vast array of current assertions that low dose linearity is no longer appropriate for low dose cancer risk assessment but suggests that non-carcinogen risk assessment practices may need to be reconsidered as well…While the BELLE initiative has focused on an assessment of the wide possible range of dose response relationships in the low dose zone, the BELLE Newsletter has published a series of papers that have challenged the notion of low dose linearity based on theoretical foundation, as well as experimental/epidemiological and mechanistic studies. Thus, given the potentially controversial, yet substantial, nature of the Crawford and Wilson paper, it was felt that there should be a broad discussion of this paper since it is at the heart of critical issues in the risk assessment process. Consequently, Dr. Richard Wilson was contacted and asked to prepare a shortened form (e.g., 10 pages down from over 30 pages) of the original article. He also agreed to consider and respond to the comments of a number of external experts that would be invited to offer independent commentary on this paper. The reviewers were sent both the original (longer) version and the shortened form which is now published in the Newsletter. We trust that you will find this discussion both challenging and enlightening.
↑ Thayer KA, Melnick R, Huff J, Burns K, Davis D. (2006) Hormesis: A New Religion? Environmental Health Perspectives Nov;114(11):A632-3. PMID 17107829 PMCID: PMC 1665404.
↑ Cook R, Calabrese EJ. (2006) The importance of hormesis to public health. Environ Health Perspect 114:1631–1635; [Online 10 July 2006].
↑ Thayer KA, Melnick R, Burns K, Davis D, Huff J. (2005) Fundamental flaws of hormesis for public health decisions. Environ Health Perspect 113:1271-1276.
↑ Calabrese EJ, Cook RR. 2005. Hormesis: how it could affect the risk assessment process. Hum Exp Toxicol 24(5):265-270.
↑ Calabrese EJ, Baldwin LA. (2003) Hormesis: the dose-response revolution. Annu Rev Pharmacol Toxicol 43:175-197.
↑ ^22.0 ^22.1 ^22.2 ^22.3 ^22.4 A.R.D. Stebbing, Ph.D. (1997) A Theory for Growth Hormesis. BELLE Newsletter Vol 6, No. 1, September 1997.
↑ Note: The editors divided this excerpt of Stebbing into paragraphs for easier reading.
↑ Townsend, J.F. & Luckey, T.D., 1960. Hormoligosis in pharmacology. J. Am. Med. Assoc., 173: 44-48. Waddington, C.H., 1977. Tools for Thought. London: Jonathan Cape.
↑ Schultz, H., 1888. Ueber Hefegifte. Pflugers Archiv fur die gesamte Physiologie des Menschen und der Tierre, 42, 517-541.
↑ Hueppe, F., 1896. The Principles of Bacteriology. Chicago Open Court.
↑ Southam, C.M. & Ehrlich, J., 1943. Effects of extracts western red cedar heartwood on certain wood-decaying fungi in culture. Phytopathology, 33: 5517-524.
↑
Miller WS, Green CA, Kitchen H. (1945) Biphasic action of penicillin and other similar sulphonamides. Nature, Lond., 155, 210-211.
- First paragraph: SUBSTANCES generally acknowledged as being toxic to cells may have an opposite effect in higher dilution. This biphasic action inhibition in high concentrations and stimulation in low concentrations has been observed with a wide variety of substances, including narcotics, cyanide, pyrithiaminel and sulphonamides [citation given]. There is ample evidence that low concentrations of the last group stimulate bacterial growth; and it would appear that the period of active proliferation, which frequently precedes bacteriostasis by sulphonamides in higher concentrations, is a manifestation of the same phenomenon. We here report what appears to be an expression of the same effect occurring with penicillin.
↑ Davis, H.C. & Hidu, H., 1969. Effects of pesticides on embryonic development of clams and oysters and on survival and growth of the larvae. Fish Bull. Fish Wildl. Serv. U.S., 67: 393-404.
↑ Luckey, T.D., 1956. Mode of action of antibiotics evidence from germ - free birds. In: 1st International Conference on the Use of Antibiotics in Agriculture. p135. National Academy of Sciences, Washington DC.
↑ ^31.0 ^31.1 Edward J. Calabrese and Linda A. Baldwin. (2002) PART 2: PROPOSING A DEFINITION OF HORMESIS: DEFINING HORMESIS. BELLE Newsletter. A Publication of the Northeast Regional Environmental Public Health Center, University of Massachusetts, School of Public Health, Amherst, MA 01003. Vol. 10, No. 2, February 2002, ISSN 1092-4736. Full-Text Online
↑ Vaiserman AM. (2010) Hormesis, adaptive epigenetic reorganization, and implications for human health and longevity. Dose Response 2010;8:16-21. From Abstract: Evidence supporting that hormetic-like effects may be the result of a generalized whole-organism adaptive epigenetic response is reviewed. Specific hormesis-inducing interventions during development would allow to achieve an optimal balance between activation and repression of various genes and thus to prevent age-related degenerative diseases and slow aging.
↑
Schmeisser S, Zarse K, Ristow M. (2011) Lonidamine extends lifespan of adult Caenorhabditis elegans by increasing the formation of mitochondrial reactive oxygen species. Horm Metab Res 43:687-92.
- "The aim of the study was to test whether pharmaceutical concentrations of the glycolytic inhibitor lonidamine are capable of extending lifespan in a nematodal model organism for aging processes, the roundworm Caenorhabditis elegans...Lonidamine significantly extends both median and maximum lifespan of C. elegans...Moreover, the compound increases paraquat stress resistance, and promotes mitochondrial respiration, culminating in increased formation of reactive oxygen species (ROS). Extension of lifespan requires activation of pmk-1, an orthologue of p38 MAP kinase, and is abolished by co-application of an antioxidant, indicating that increased ROS formation is required for the extension of lifespan by lonidamine. Consistent with the concept of mitohormesis, lonidamine is capable of promoting longevity in a pmk-1 sensitive manner by increasing formation of ROS."
↑
Ristow M, Schmeisser S. (2011) Extending life span by increasing oxidative stress. Free Radic Biol Med 51:327-36.
- "This review aims to summarize published evidence that several longevity-promoting interventions may converge by causing an activation of mitochondrial oxygen consumption to promote increased formation of reactive oxygen species (ROS). These serve as molecular signals to exert downstream effects to ultimately induce endogenous defense mechanisms culminating in increased stress resistance and longevity, an adaptive response more specifically named mitochondrial hormesis or mitohormesis. Consistently, we here summarize findings that antioxidant supplements that prevent these ROS signals interfere with the health-promoting and life-span-extending capabilities of calorie restriction and physical exercise. Taken together and consistent with ample published evidence, the findings summarized here question Harman's Free Radical Theory of Aging and rather suggest that ROS act as essential signaling molecules to promote metabolic health and longevity."
↑ ^35.0 ^35.1 Calabrese EJ, Blain RB. (2009) Hormesis and plant biology. Environ Pollut 157:42-48.
↑ Young-Joon Surh. (2011) Xenohormesis mechanisms underlying chemopreventive effects of some dietary phytochemicals. Ann. N.Y. Acad. Sci. 1229 :1–6.
↑ ^37.0 ^37.1 Konrad T. Howitz, David A. Sinclair. (2008) Xenohormesis: Sensing the Chemical Cues of Other Species. Cell 133:387-391
↑ Ames BN, Profet M, Gold LS. (1990) Dietary pesticides (99.99% all natural). Proc. Natl. Acad. Sci. USA 87:7777-7781.
↑ Oberbaum M, Samuels N, Singer SR. (2005) Hormesis is not homeopathy. Toxicology and Applied Pharmacology 206:365– 366.

[mattsonageing08-1] 1.0 ^1.1 ^1.2 ^1.3 ^1.4 Mattson M (2008) Hormesis defined. Ageing Res.Rev. 7:1-7 PMID 18162444.
Abstract: Hormesis is a term used by toxicologists to refer to a biphasic dose-response to an environmental agent characterized by a low dose stimulation or beneficial effect and a high dose inhibitory or toxic effect. In biology and medicine, hormesis is defined as an adaptive response of cells and organisms to a moderate (usually intermittent) stress. Examples include ischemic preconditioning, exercise, dietary energy restriction and exposures to low doses of certain phytochemicals. Recent findings have elucidated the cellular signaling pathways and molecular mechanisms that mediate hormetic responses which typically involve enzymes such as kinases and deacetylases, and transcription factors such as Nrf-2 and NF-kappaB. As a result, cells increase their production of cytoprotective and restorative proteins including growth factors, phase 2 and antioxidant enzymes, and protein chaperones. A better understanding of hormesis mechanisms at the cellular and molecular levels is leading to and to novel approaches for the prevention and treatment of many different diseases.

[2] Abstract: Hormesis is a term used by toxicologists to refer to a biphasic dose-response to an environmental agent characterized by a low dose stimulation or beneficial effect and a high dose inhibitory or toxic effect. In biology and medicine, hormesis is defined as an adaptive response of cells and organisms to a moderate (usually intermittent) stress. Examples include ischemic preconditioning, exercise, dietary energy restriction and exposures to low doses of certain phytochemicals. Recent findings have elucidated the cellular signaling pathways and molecular mechanisms that mediate hormetic responses which typically involve enzymes such as kinases and deacetylases, and transcription factors such as Nrf-2 and NF-kappaB. As a result, cells increase their production of cytoprotective and restorative proteins including growth factors, phase 2 and antioxidant enzymes, and protein chaperones. A better understanding of hormesis mechanisms at the cellular and molecular levels is leading to and to novel approaches for the prevention and treatment of many different diseases.

[2] Johnson MD.(2010) Human Biology: Concepts and Current Issues 6th ed. Boston: Benjamin Cummings. ISBN 978-0-321-70167-1.

[olsen2011-3] Olsen CM. (2011) Natural rewards, neuroplasticity, and non-drug addictions. 'Neuropharmacology 61:1109-1122.

[4] Chadwick W, Maudsley S. (2010) The Devil Is in the Dose: Complexity of Receptor Systems and Responses. In: Mark P. Mattson and Edward J. Calabrese, editors. Hormesis: A Revolution in Biology, Toxicology and Medicine. Springer. ISBN 978-1-60761-494-4.

[hively2002-5] Hively W (2002) Is Radiation Good For You? Discover Dec. 1.

[mattsonns08-6] 6.0 ^6.1 ^6.2 ^6.3 Mattson M, Calabrese E (2008) When a little poison is good for you. New Scientist 9 August 2008. pp. 34-39.
From the article: In 2008, Mark Mattson was chief of the laboratory of Neurosciences at the US National Institute on Aging and a professor of neurosciences at John Hopkins University in Baltimore, Maryland. He was then the most highly cited neuroscientist in the world. Edward Calabrese was a professor of toxicology at the University of Massachusetts in Amherst.

[8] From the article: In 2008, Mark Mattson was chief of the laboratory of Neurosciences at the US National Institute on Aging and a professor of neurosciences at John Hopkins University in Baltimore, Maryland. He was then the most highly cited neuroscientist in the world. Edward Calabrese was a professor of toxicology at the University of Massachusetts in Amherst.

[crawford1994-7] Crawford DR, Davies KJA (1994) Adaptive Response and Oxidative Stress. Environ Health Perspect 102(Suppl 10) :25-28.
Abstract:The ability of a cell, tissue, or organism to better resist stress damage by prior exposure to a lesser amount of stress is known as adaptive response. It is observed in all organisms in response to a number of different cytotoxic agents. One of these agents, oxidative stress, is known to induce an adaptive response in bacteria that is accompanied by the induction of many proteins. De novo protein synthesis is required for adaptive response to oxidative and other types of stress, indicating that newly synthesized protective proteins are necessary for adaptation. Adaptive response to oxidative stress also has been observed in mammalian cells. Several studies suggest it is necessary to first preexpose mammalian cells to a somewhat toxic oxidative stress in order to observe significant resistance to a subsequent highly lethal dose of oxidant. Cross-resistance of oxidatively stressed cells to other toxic agents including - and X-irradiation, heat shock, aldehydes, heavy metals, MNNG, N-ethylmaleimide, and heme also has been reported. Understanding oxidant adaptive response in more detail and identifying the protective proteins involved may prove to be of clinical benefit.

[10] Abstract:The ability of a cell, tissue, or organism to better resist stress damage by prior exposure to a lesser amount of stress is known as adaptive response. It is observed in all organisms in response to a number of different cytotoxic agents. One of these agents, oxidative stress, is known to induce an adaptive response in bacteria that is accompanied by the induction of many proteins. De novo protein synthesis is required for adaptive response to oxidative and other types of stress, indicating that newly synthesized protective proteins are necessary for adaptation. Adaptive response to oxidative stress also has been observed in mammalian cells. Several studies suggest it is necessary to first preexpose mammalian cells to a somewhat toxic oxidative stress in order to observe significant resistance to a subsequent highly lethal dose of oxidant. Cross-resistance of oxidatively stressed cells to other toxic agents including - and X-irradiation, heat shock, aldehydes, heavy metals, MNNG, N-ethylmaleimide, and heme also has been reported. Understanding oxidant adaptive response in more detail and identifying the protective proteins involved may prove to be of clinical benefit.

[calabreseblain2005-8] Calabrese EJ, Blain R (2005) [http://dx.doi.org/10.1016/j.taap.2004.06.023 The occurrence of hormetic dose responses in the toxicological literature, the hormesis database: an overview. Toxicol. Appl. Pharmacol. 202:289-301 PMID 15667834.
Abstract: A relational retrieval database has been developed compiling toxicological studies assessing the occurrence of hormetic dose responses and their quantitative characteristics. This database permits an evaluation of these studies over numerous parameters, including study design and dose-response features and physical/chemical properties of the agents. The database contains approximately 5600 dose-response relationships satisfying evaluative criteria for hormesis across over approximately 900 agents from a broadly diversified spectrum of chemical classes and physical agents. The assessment reveals that hormetic dose-response relationships occur in males and females of numerous animal models in all principal age groups as well as across species displaying a broad range of differential susceptibilities to toxic agents. The biological models are extensive, including plants, viruses, bacteria, fungi, insects, fish, birds, rodents, and primates, including humans. The spectrum of endpoints displaying hormetic dose responses is also broad being inclusive of growth, longevity, numerous metabolic parameters, disease incidences (including cancer), various performance endpoints such as cognitive functions, immune responses among others. Quantitative features of the hormetic dose response reveal that the vast majority of cases display a maximum stimulatory response less than two-fold greater than the control while the width of the stimulatory response is typically less than 100-fold in dose range immediately contiguous with the toxicological NO(A)EL. The database also contains a quantitative evaluation component that differentiates among the various dose responses concerning the strength of the evidence supporting a hormetic conclusion based on study design features, magnitude of the stimulatory response, statistical significance, and reproducibility of findings.

[12] Abstract: A relational retrieval database has been developed compiling toxicological studies assessing the occurrence of hormetic dose responses and their quantitative characteristics. This database permits an evaluation of these studies over numerous parameters, including study design and dose-response features and physical/chemical properties of the agents. The database contains approximately 5600 dose-response relationships satisfying evaluative criteria for hormesis across over approximately 900 agents from a broadly diversified spectrum of chemical classes and physical agents. The assessment reveals that hormetic dose-response relationships occur in males and females of numerous animal models in all principal age groups as well as across species displaying a broad range of differential susceptibilities to toxic agents. The biological models are extensive, including plants, viruses, bacteria, fungi, insects, fish, birds, rodents, and primates, including humans. The spectrum of endpoints displaying hormetic dose responses is also broad being inclusive of growth, longevity, numerous metabolic parameters, disease incidences (including cancer), various performance endpoints such as cognitive functions, immune responses among others. Quantitative features of the hormetic dose response reveal that the vast majority of cases display a maximum stimulatory response less than two-fold greater than the control while the width of the stimulatory response is typically less than 100-fold in dose range immediately contiguous with the toxicological NO(A)EL. The database also contains a quantitative evaluation component that differentiates among the various dose responses concerning the strength of the evidence supporting a hormetic conclusion based on study design features, magnitude of the stimulatory response, statistical significance, and reproducibility of findings.

[calabresemed-9] 9.0 ^9.1 Calabrese EJ (2008) Hormesis and medicine. Br J Clin Pharmacol PMID 18662293.
Abstract: Evidence is presented which supports the conclusion that the hormetic dose-response model is the most common and fundamental in the biological and biomedical sciences, being highly generalizable across biological model, endpoint measured and chemical class and physical agent. The paper provides a broad spectrum of applications of the hormesis concept for clinical medicine including anxiety, seizure, memory, stroke, cancer chemotherapy, dermatological processes such as hair growth, osteoporosis, ocular diseases, including retinal detachment, statin effects on cardiovascular function and tumour development, benign prostate enlargement, male sexual behaviours/dysfunctions, and prion diseases.

[14] Abstract: Evidence is presented which supports the conclusion that the hormetic dose-response model is the most common and fundamental in the biological and biomedical sciences, being highly generalizable across biological model, endpoint measured and chemical class and physical agent. The paper provides a broad spectrum of applications of the hormesis concept for clinical medicine including anxiety, seizure, memory, stroke, cancer chemotherapy, dermatological processes such as hair growth, osteoporosis, ocular diseases, including retinal detachment, statin effects on cardiovascular function and tumour development, benign prostate enlargement, male sexual behaviours/dysfunctions, and prion diseases.

[stumpf06-10] Stumpf WE (2006) The dose makes the medicine. Drug Discov Today 11:550-5 PMID 16713907.
Abstract: Dose and time considerations in the development and use of a drug are important for assessing actions and side effects, as well as predictions of safety and toxicity. This article deals with epistemological aspects of dose selection by probing into the linguistic and cultural roots for the measure of medicine mediated by the medical doctor. Because toxicity is related to dose, historic and recent views suggest that less can be more. At low, medium and high dose levels, effects can differ not only quantitatively but also qualitatively. Dose-related target activation and recognition of enantiodromic thresholds between beneficial and toxic effects require elucidation of underlying events. Such studies, including hormesis and microdosing, call for extended ADME procedures with high-resolution methods in addition to the current low-resolution approaches. Improved information of drug logistics and target pharmacokinetics enables effective drug selection, dose determination and prediction. It also allows considerations of systems biology [i.e. integral (gestalt) pharmacology] exemplified by the drug homunculus, as in the case of vitamin D, that might lead to new paradigms and drug design.

[16] Abstract: Dose and time considerations in the development and use of a drug are important for assessing actions and side effects, as well as predictions of safety and toxicity. This article deals with epistemological aspects of dose selection by probing into the linguistic and cultural roots for the measure of medicine mediated by the medical doctor. Because toxicity is related to dose, historic and recent views suggest that less can be more. At low, medium and high dose levels, effects can differ not only quantitatively but also qualitatively. Dose-related target activation and recognition of enantiodromic thresholds between beneficial and toxic effects require elucidation of underlying events. Such studies, including hormesis and microdosing, call for extended ADME procedures with high-resolution methods in addition to the current low-resolution approaches. Improved information of drug logistics and target pharmacokinetics enables effective drug selection, dose determination and prediction. It also allows considerations of systems biology [i.e. integral (gestalt) pharmacology] exemplified by the drug homunculus, as in the case of vitamin D, that might lead to new paradigms and drug design.

[stebbing1987-11] Stebbing AR. (1987) Growth hormesis: a by-product of control. Health Phys 52:543-7
Abstract: Data from experiments, in which colonies of a hydroid, Laomedea flexuosa, were exposed to a range of Cu2+ concentrations and a marine yeast, Rhodotorula rubra, was exposed to a range of Cd2+ concentrations, not only exhibit hormesis, but also suggest how its occurrence in growth experiments might be explained. When growth data are considered as normalized specific rates against a time base, their oscillatory form indicates the output of a growth regulatory mechanism whose behaviour can be used to interpret the typical concentration-response curve exhibiting hormesis. Advantages may be conferred upon organisms whose growth control mechanisms overcorrect in response to low levels of inhibitory loading by toxic agents (stimulus), while at higher concentrations it is the overloading of such control mechanisms that results in the threshold in concentration-response curves (inhibition). It is suggested that if different examples of hormesis share a common explanation, it lies in the behaviour of homeostatic and homeorhetic feedback mechanisms, which respond to perturbation non-specifically and may overcorrect for adaptive reasons to low levels of inhibitory challenge.

[18] Abstract: Data from experiments, in which colonies of a hydroid, Laomedea flexuosa, were exposed to a range of Cu2+ concentrations and a marine yeast, Rhodotorula rubra, was exposed to a range of Cd2+ concentrations, not only exhibit hormesis, but also suggest how its occurrence in growth experiments might be explained. When growth data are considered as normalized specific rates against a time base, their oscillatory form indicates the output of a growth regulatory mechanism whose behaviour can be used to interpret the typical concentration-response curve exhibiting hormesis. Advantages may be conferred upon organisms whose growth control mechanisms overcorrect in response to low levels of inhibitory loading by toxic agents (stimulus), while at higher concentrations it is the overloading of such control mechanisms that results in the threshold in concentration-response curves (inhibition). It is suggested that if different examples of hormesis share a common explanation, it lies in the behaviour of homeostatic and homeorhetic feedback mechanisms, which respond to perturbation non-specifically and may overcorrect for adaptive reasons to low levels of inhibitory challenge.

[stebbing2000-12] 12.0 ^12.1 Stebbing AR. (2000) Hormesis: interpreting the beta-curve using control theory. J Appl Toxicol 20:93-101.
Abstract: Data from experiments exposing colonial hydroids to toxic growth inhibitors have provided evidence of growth control mechanisms that respond adaptively to counter toxic inhibition. Analysis of growth data and the development of simulation models provide an interpretation of both alpha- and beta-curves. The hypothesis also suggests that hormesis is related to adaptation by growth control mechanisms that confer tolerance to subsequent exposure.

[20] Abstract: Data from experiments exposing colonial hydroids to toxic growth inhibitors have provided evidence of growth control mechanisms that respond adaptively to counter toxic inhibition. Analysis of growth data and the development of simulation models provide an interpretation of both alpha- and beta-curves. The hypothesis also suggests that hormesis is related to adaptation by growth control mechanisms that confer tolerance to subsequent exposure.

[zhang2008-13] Zhang Q, Pi J, Jarabek AM, Clewell III HJ, Anderson ME. (2008) Hormesis and adaptive cellular control systems. Dose-Response 6:196-208.
Abstract: Hormetic dose response occurs for many endpoints associated with exposures of biological organisms to environmental stressors. Cell-based U- or inverted U-shaped responses may derive from common processes involved in activation of adaptive responses required to protect cells from stressful environments. These adaptive pathways extend the region of cellular homeostasis and are protective against ultimate cell, organ, and system toxicity. However, the activation of stress responses carries a significant energetic cost to the cell, leading to alterations of a variety of basal cellular functions in adapted or stressed cells. This tradeoff of resources between the unstressed and adapted states may lead to U-or inverted U-shaped dose response curves for some precursor endpoints. We examine this general hypothesis with chlorine, a prototype oxidative stressor, using a combination of cellular studies with gene expression analysis of response pathways and with computational modeling of activation of control networks. Discrete cellular states are expected as a function of exposure concentration and duration. These cellular states include normal functioning state, adaptive and stressed states at mild to intermediate exposures, and overt toxicity in the presence of an overwhelming concentration of stressors. These transitions can be used to refine default risk assessment practices that do not currently accommodate adaptive responses.

[22] Abstract: Hormetic dose response occurs for many endpoints associated with exposures of biological organisms to environmental stressors. Cell-based U- or inverted U-shaped responses may derive from common processes involved in activation of adaptive responses required to protect cells from stressful environments. These adaptive pathways extend the region of cellular homeostasis and are protective against ultimate cell, organ, and system toxicity. However, the activation of stress responses carries a significant energetic cost to the cell, leading to alterations of a variety of basal cellular functions in adapted or stressed cells. This tradeoff of resources between the unstressed and adapted states may lead to U-or inverted U-shaped dose response curves for some precursor endpoints. We examine this general hypothesis with chlorine, a prototype oxidative stressor, using a combination of cellular studies with gene expression analysis of response pathways and with computational modeling of activation of control networks. Discrete cellular states are expected as a function of exposure concentration and duration. These cellular states include normal functioning state, adaptive and stressed states at mild to intermediate exposures, and overt toxicity in the presence of an overwhelming concentration of stressors. These transitions can be used to refine default risk assessment practices that do not currently accommodate adaptive responses.

[stebbing1998-14] Stebbing AR. (1998) A theory for growth hormesis. Mutat Res 403: 249-58. PMID 9726025.
Excerpt: The hypothesis tested therefore was that hormesis is a consequence of an adaptive response common to biological systems to the inhibitory effect that the different agents have in common at higher concentrations.

[24] Excerpt: The hypothesis tested therefore was that hormesis is a consequence of an adaptive response common to biological systems to the inhibitory effect that the different agents have in common at higher concentrations.

[calabresecrittox01-15] Calabrese EJ. (2001) Overcompensation stimulation: A mechanism for hormetic effects. Crit Rev Toxicol 31: 425-70.
Abstract: Whether hormetic responses result from a direct or an overcompensation type of stimulatory response has been an unresolved and contentious issue in both radiation and chemical toxicology. The goal of the present article is to identify numerous examples of overcompensation stimulation in the biological/biomedical literature and to evaluate their descriptive and quantitative features. The findings provide support for the hypothesis that hormetic dose-response relationships from a broad array of biological models can occur after an initial disruption in homeostasis. The finding also demonstrates the significant role of temporal factors in the assessment of dose response relationships.

[26] Abstract: Whether hormetic responses result from a direct or an overcompensation type of stimulatory response has been an unresolved and contentious issue in both radiation and chemical toxicology. The goal of the present article is to identify numerous examples of overcompensation stimulation in the biological/biomedical literature and to evaluate their descriptive and quantitative features. The findings provide support for the hypothesis that hormetic dose-response relationships from a broad array of biological models can occur after an initial disruption in homeostasis. The finding also demonstrates the significant role of temporal factors in the assessment of dose response relationships.

[16] LOW DOSE LINEARITY: THE RULE OR THE EXCEPTION. BELLE Newsletter Vol 6, No. 1, March 1997.
From the Introduction: A recently published paper by Martha Crawford and Richard Wilson entitled "Low-Dose Linearity: The Rule or the Exception? " in the journal Human and Ecological Risk Assessment, Vol. 2, No. 2, 1996 argued that low dose linearity of the dose response curve might be the rule rather than the exception. While the assumption of low dose linearity has been widely accepted in concept and implemented in U.S. federal risk assessment practices for radiation and chemical carcinogens, it has not been believed to apply to non-carcinogens that have been accepted without controversy as having thresholds below which no adverse effects would be expected. However, Crawford and Wilson contend that the concept of low dose linearity is broadly generalizable and should apply to non-carcinogens as well. Their article, which urges a reconsideration of how background response is considered in risk assessment, challenges not only the vast array of current assertions that low dose linearity is no longer appropriate for low dose cancer risk assessment but suggests that non-carcinogen risk assessment practices may need to be reconsidered as well…While the BELLE initiative has focused on an assessment of the wide possible range of dose response relationships in the low dose zone, the BELLE Newsletter has published a series of papers that have challenged the notion of low dose linearity based on theoretical foundation, as well as experimental/epidemiological and mechanistic studies. Thus, given the potentially controversial, yet substantial, nature of the Crawford and Wilson paper, it was felt that there should be a broad discussion of this paper since it is at the heart of critical issues in the risk assessment process. Consequently, Dr. Richard Wilson was contacted and asked to prepare a shortened form (e.g., 10 pages down from over 30 pages) of the original article. He also agreed to consider and respond to the comments of a number of external experts that would be invited to offer independent commentary on this paper. The reviewers were sent both the original (longer) version and the shortened form which is now published in the Newsletter. We trust that you will find this discussion both challenging and enlightening.

[28] From the Introduction: A recently published paper by Martha Crawford and Richard Wilson entitled "Low-Dose Linearity: The Rule or the Exception? " in the journal Human and Ecological Risk Assessment, Vol. 2, No. 2, 1996 argued that low dose linearity of the dose response curve might be the rule rather than the exception. While the assumption of low dose linearity has been widely accepted in concept and implemented in U.S. federal risk assessment practices for radiation and chemical carcinogens, it has not been believed to apply to non-carcinogens that have been accepted without controversy as having thresholds below which no adverse effects would be expected. However, Crawford and Wilson contend that the concept of low dose linearity is broadly generalizable and should apply to non-carcinogens as well. Their article, which urges a reconsideration of how background response is considered in risk assessment, challenges not only the vast array of current assertions that low dose linearity is no longer appropriate for low dose cancer risk assessment but suggests that non-carcinogen risk assessment practices may need to be reconsidered as well…While the BELLE initiative has focused on an assessment of the wide possible range of dose response relationships in the low dose zone, the BELLE Newsletter has published a series of papers that have challenged the notion of low dose linearity based on theoretical foundation, as well as experimental/epidemiological and mechanistic studies. Thus, given the potentially controversial, yet substantial, nature of the Crawford and Wilson paper, it was felt that there should be a broad discussion of this paper since it is at the heart of critical issues in the risk assessment process. Consequently, Dr. Richard Wilson was contacted and asked to prepare a shortened form (e.g., 10 pages down from over 30 pages) of the original article. He also agreed to consider and respond to the comments of a number of external experts that would be invited to offer independent commentary on this paper. The reviewers were sent both the original (longer) version and the shortened form which is now published in the Newsletter. We trust that you will find this discussion both challenging and enlightening.

[thayer2006-17] Thayer KA, Melnick R, Huff J, Burns K, Davis D. (2006) Hormesis: A New Religion? Environmental Health Perspectives Nov;114(11):A632-3. PMID 17107829 PMCID: PMC 1665404.

[cook2006-18] Cook R, Calabrese EJ. (2006) The importance of hormesis to public health. Environ Health Perspect 114:1631–1635; [Online 10 July 2006].

[thayer2005-19] Thayer KA, Melnick R, Burns K, Davis D, Huff J. (2005) Fundamental flaws of hormesis for public health decisions. Environ Health Perspect 113:1271-1276.

[calabresecook2005-20] Calabrese EJ, Cook RR. 2005. Hormesis: how it could affect the risk assessment process. Hum Exp Toxicol 24(5):265-270.

[calabresebaldwin2003a-21] Calabrese EJ, Baldwin LA. (2003) Hormesis: the dose-response revolution. Annu Rev Pharmacol Toxicol 43:175-197.

[stebbinghx-22] 22.0 ^22.1 ^22.2 ^22.3 ^22.4 A.R.D. Stebbing, Ph.D. (1997) A Theory for Growth Hormesis. BELLE Newsletter Vol 6, No. 1, September 1997.

[23] Note: The editors divided this excerpt of Stebbing into paragraphs for easier reading.

[townsend1960-24] Townsend, J.F. & Luckey, T.D., 1960. Hormoligosis in pharmacology. J. Am. Med. Assoc., 173: 44-48. Waddington, C.H., 1977. Tools for Thought. London: Jonathan Cape.

[schultz1888-25] Schultz, H., 1888. Ueber Hefegifte. Pflugers Archiv fur die gesamte Physiologie des Menschen und der Tierre, 42, 517-541.

[hueppe1896-26] Hueppe, F., 1896. The Principles of Bacteriology. Chicago Open Court.

[southam1943-27] Southam, C.M. & Ehrlich, J., 1943. Effects of extracts western red cedar heartwood on certain wood-decaying fungi in culture. Phytopathology, 33: 5517-524.

[miller1945-28] Miller WS, Green CA, Kitchen H. (1945) Biphasic action of penicillin and other similar sulphonamides. Nature, Lond., 155, 210-211.
First paragraph: SUBSTANCES generally acknowledged as being toxic to cells may have an opposite effect in higher dilution. This biphasic action inhibition in high concentrations and stimulation in low concentrations has been observed with a wide variety of substances, including narcotics, cyanide, pyrithiaminel and sulphonamides [citation given]. There is ample evidence that low concentrations of the last group stimulate bacterial growth; and it would appear that the period of active proliferation, which frequently precedes bacteriostasis by sulphonamides in higher concentrations, is a manifestation of the same phenomenon. We here report what appears to be an expression of the same effect occurring with penicillin.

[41] First paragraph: SUBSTANCES generally acknowledged as being toxic to cells may have an opposite effect in higher dilution. This biphasic action inhibition in high concentrations and stimulation in low concentrations has been observed with a wide variety of substances, including narcotics, cyanide, pyrithiaminel and sulphonamides [citation given]. There is ample evidence that low concentrations of the last group stimulate bacterial growth; and it would appear that the period of active proliferation, which frequently precedes bacteriostasis by sulphonamides in higher concentrations, is a manifestation of the same phenomenon. We here report what appears to be an expression of the same effect occurring with penicillin.

[davis1969-29] Davis, H.C. & Hidu, H., 1969. Effects of pesticides on embryonic development of clams and oysters and on survival and growth of the larvae. Fish Bull. Fish Wildl. Serv. U.S., 67: 393-404.

[luckey1956-30] Luckey, T.D., 1956. Mode of action of antibiotics evidence from germ - free birds. In: 1st International Conference on the Use of Antibiotics in Agriculture. p135. National Academy of Sciences, Washington DC.

[calabresebellefeb02-31] 31.0 ^31.1 Edward J. Calabrese and Linda A. Baldwin. (2002) PART 2: PROPOSING A DEFINITION OF HORMESIS: DEFINING HORMESIS. BELLE Newsletter. A Publication of the Northeast Regional Environmental Public Health Center, University of Massachusetts, School of Public Health, Amherst, MA 01003. Vol. 10, No. 2, February 2002, ISSN 1092-4736. Full-Text Online

[vaiserman2010-32] Vaiserman AM. (2010) Hormesis, adaptive epigenetic reorganization, and implications for human health and longevity. Dose Response 2010;8:16-21. From Abstract: Evidence supporting that hormetic-like effects may be the result of a generalized whole-organism adaptive epigenetic response is reviewed. Specific hormesis-inducing interventions during development would allow to achieve an optimal balance between activation and repression of various genes and thus to prevent age-related degenerative diseases and slow aging.

[schmeisser2011-33] Schmeisser S, Zarse K, Ristow M. (2011) Lonidamine extends lifespan of adult Caenorhabditis elegans by increasing the formation of mitochondrial reactive oxygen species. Horm Metab Res 43:687-92.
"The aim of the study was to test whether pharmaceutical concentrations of the glycolytic inhibitor lonidamine are capable of extending lifespan in a nematodal model organism for aging processes, the roundworm Caenorhabditis elegans...Lonidamine significantly extends both median and maximum lifespan of C. elegans...Moreover, the compound increases paraquat stress resistance, and promotes mitochondrial respiration, culminating in increased formation of reactive oxygen species (ROS). Extension of lifespan requires activation of pmk-1, an orthologue of p38 MAP kinase, and is abolished by co-application of an antioxidant, indicating that increased ROS formation is required for the extension of lifespan by lonidamine. Consistent with the concept of mitohormesis, lonidamine is capable of promoting longevity in a pmk-1 sensitive manner by increasing formation of ROS."

[47] "The aim of the study was to test whether pharmaceutical concentrations of the glycolytic inhibitor lonidamine are capable of extending lifespan in a nematodal model organism for aging processes, the roundworm Caenorhabditis elegans...Lonidamine significantly extends both median and maximum lifespan of C. elegans...Moreover, the compound increases paraquat stress resistance, and promotes mitochondrial respiration, culminating in increased formation of reactive oxygen species (ROS). Extension of lifespan requires activation of pmk-1, an orthologue of p38 MAP kinase, and is abolished by co-application of an antioxidant, indicating that increased ROS formation is required for the extension of lifespan by lonidamine. Consistent with the concept of mitohormesis, lonidamine is capable of promoting longevity in a pmk-1 sensitive manner by increasing formation of ROS."

[ristow2011-34] Ristow M, Schmeisser S. (2011) Extending life span by increasing oxidative stress. Free Radic Biol Med 51:327-36.
"This review aims to summarize published evidence that several longevity-promoting interventions may converge by causing an activation of mitochondrial oxygen consumption to promote increased formation of reactive oxygen species (ROS). These serve as molecular signals to exert downstream effects to ultimately induce endogenous defense mechanisms culminating in increased stress resistance and longevity, an adaptive response more specifically named mitochondrial hormesis or mitohormesis. Consistently, we here summarize findings that antioxidant supplements that prevent these ROS signals interfere with the health-promoting and life-span-extending capabilities of calorie restriction and physical exercise. Taken together and consistent with ample published evidence, the findings summarized here question Harman's Free Radical Theory of Aging and rather suggest that ROS act as essential signaling molecules to promote metabolic health and longevity."

[49] "This review aims to summarize published evidence that several longevity-promoting interventions may converge by causing an activation of mitochondrial oxygen consumption to promote increased formation of reactive oxygen species (ROS). These serve as molecular signals to exert downstream effects to ultimately induce endogenous defense mechanisms culminating in increased stress resistance and longevity, an adaptive response more specifically named mitochondrial hormesis or mitohormesis. Consistently, we here summarize findings that antioxidant supplements that prevent these ROS signals interfere with the health-promoting and life-span-extending capabilities of calorie restriction and physical exercise. Taken together and consistent with ample published evidence, the findings summarized here question Harman's Free Radical Theory of Aging and rather suggest that ROS act as essential signaling molecules to promote metabolic health and longevity."

[calabreseplantbiol-35] 35.0 ^35.1 Calabrese EJ, Blain RB. (2009) Hormesis and plant biology. Environ Pollut 157:42-48.

[surhxeno1-36] Young-Joon Surh. (2011) Xenohormesis mechanisms underlying chemopreventive effects of some dietary phytochemicals. Ann. N.Y. Acad. Sci. 1229 :1–6.

[horwitzxeno1-37] 37.0 ^37.1 Konrad T. Howitz, David A. Sinclair. (2008) Xenohormesis: Sensing the Chemical Cues of Other Species. Cell 133:387-391

[amesxeno1-38] Ames BN, Profet M, Gold LS. (1990) Dietary pesticides (99.99% all natural). Proc. Natl. Acad. Sci. USA 87:7777-7781.

[39] Oberbaum M, Samuels N, Singer SR. (2005) Hormesis is not homeopathy. Toxicology and Applied Pharmacology 206:365– 366.

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+In [[toxicology]], '''hormesis''' refers to a quantitative and qualitative dose-response relationship&mdash;also called a concentration-effect relationship&mdash;between the amount of exposure of an organism to an environmental agent and the organism's biological response, a relationship in which the response at certain low concentrations of agent occurs in a direction opposite to that expected from the response observed at higher concentrations&mdash;i.e., with increasing concentration of the environmental agent the response is ''biphasic''.<ref name=mattsonageing08>Mattson M (2008) [http://dx.doi.org/10.1016/j.arr.2007.08.007 Hormesis defined.] ''Ageing Res.Rev.'' 7:1-7 PMID 18162444.
-'''<u>Note:</u>''' ''Text in font-color'' <font color=#000099>Blue</font> ''link to articles in Citizendium; text in font-color'' <font color=#810541>Maroon</font> ''link to articles not yet started'';<br>
+*<font face="Gill Sans MT">'''<u>Abstract:</u>'''&nbsp;Hormesis is a term used by toxicologists to refer to a biphasic dose-response to an environmental agent characterized by a low dose stimulation or beneficial effect and a high dose inhibitory or toxic effect. In biology and medicine, hormesis is defined as an adaptive response of cells and organisms to a moderate (usually intermittent) [[stress]]. Examples include ischemic preconditioning, exercise, dietary energy restriction and exposures to low doses of certain phytochemicals. Recent findings have elucidated the cellular signaling pathways and molecular mechanisms that mediate hormetic responses which typically involve enzymes such as kinases and deacetylases, and transcription factors such as Nrf-2 and NF-kappaB. As a result, cells increase their production of cytoprotective and restorative proteins including growth factors, phase 2 and antioxidant [[enzyme]]s, and protein [[chaperone]]s. A better understanding of hormesis mechanisms at the cellular and molecular levels is leading to and to novel approaches for the prevention and treatment of many different diseases.</font></ref> For example, in some cases, a [[toxin]], so-called because it ''inhibits'' a function of a biological component of the organism in certain known doses, ''stimulates'' the function of that component at lower doses. Typically, the higher dose effect inflicts injury to the organism, whereas the lower dose effect benefits it.
-''authors/editors encouraged to initiate articles not yet started. Text in italic font-color'' '''''<font color=#330066>dark-blue</font>''''' ''indicate a direct quote.''<br>
-''Text in bold font-color'' '''<font color=#660000>Dark Brown</font>''' ''used for special emphasis.''
+In physiology and medicine, hormesis also refers to an adaptation that occurs when low levels of stress from a challenge to a system renders the system more resistant to tougher challenges&mdash;a ''[[Monotonic function|non-monotonic]]'' effect.<ref name=mattsonageing08/> For example, low levels of the stress produced by regular moderate muscular exercise results in adaptation of the muscles to achieve more mass, strength, and power, enabling the exercised muscles to withstand greater loads of mass and momentum, a ''physiological'' hormetic effect reflecting an underlying ''molecular'' hormetic effect within the muscle cells.<ref>Johnson MD.(2010) ''Human Biology: Concepts and Current Issues'' 6th ed. Boston: Benjamin Cummings. ISBN 978-0-321-70167-1.</ref> Excessive exercise, however, can lead to drug-like addictive behavioral responses.<ref name=olsen2011>Olsen CM. (2011) [http://dx.doi.org/10.1016/j.neuropharm.2011.03.010 Natural rewards, neuroplasticity, and non-drug addictions]. 'Neuropharmacology'' 61:1109-1122.</ref>
-|
+==Introduction==
+{|align="right" cellpadding="10" style="background:lightgray; width:35%; border: 1px solid #aaa; margin:20px; font-size: 93%; font-family: Gill Sans MT;"
+|Alle Ding sind Gift, und nichts ohn Gift; allein die Dosis macht, dafβ ein Ding kein Gift ist.
+|-
+|All things are poison and nothing is without poison, only the dose permits something not to be poisonous.
+|-
+|&nbsp;&nbsp;&mdash;Paracelsus (Philip von Hohenheim) (1493-1541) <ref>Chadwick W, Maudsley S. (2010) The Devil Is in the Dose: Complexity of Receptor Systems and Responses. In: Mark P. Mattson and Edward J. Calabrese, editors. ''Hormesis: A Revolution in Biology, Toxicology and Medicine''. Springer. ISBN 978-1-60761-494-4.</ref>
+|-
 |}
-{{-}}
+===''Medicine or poison? Depends on dose''===
-----
+The fundamental characteristic of hormesis is its '[[Monotonic function|non-monotonic]]' or 'biphasic' feature, meaning the response to the agent in question adapts the organism to subsequent or higher doses, or changes direction with increasing doses. In respect of the latter, the low dose-range where a stimulation occurs &mdash; stimulatory zone &mdash; may have either beneficial or detrimental effect to the organism, though interest often concentrates on instances in which the low-dose effect confers benefit, the higher doses detriment. 'Stimulation' thus may refer to stimulation of benefit or detriment.
-'''Hormesis''' is a technical term used in toxicology to refer to a quantitative and qualitative dose-response, or concentration-effect, relationship in which the effect at low concentrations occurs in the opposite direction from that expected from the effect observed at higher concentrations. For example, a toxin that inhibits function of a biological component in certain known doses stimulates the function of that component at lower doses. Interest seems to concentrate on instances in which the low-dose effect confers benefit whereas the high-dose effect exhibits detriment.  Some biologists, including health science biologists, often use 'hormesis' to refer to an adaptive response of cells and organisms to various categories of 'stress', an adaptation characterized by resistance to the stressor when previously exposed to it at low levels,
+<blockquote>
+<p style="margin-left: 2.0%; margin-right: 6%; font-size: 1.0em; font-family: Trebuchet MS;">"Poisons that injure or kill at high doses can have the opposite effect at low doses, [Professor Calabrese] says, and the paradox holds true for every conceivable measure of health—growth, fertility, life span, and immune and mental function. The effect is known as hormesis, from the Greek word for excite. "The implications," [Professor Calabrese] says, "are enormous."" (Hively, 2002, speaking of biphasic effects of radiation exposure)<ref name=hively2002>Hively W (2002) [http://discovermagazine.com/2002/dec/featradiation/?searchterm=hormesis Is Radiation Good For You?] ''Discover'' Dec. 1.</ref></p>
+</blockquote>
-Biologists often begin their description of the biological phenomenon of '''hormesis''' by citing the aphorism that what doesn’t kill you makes you stronger, or the aphorism that what makes something a medicine or a poison depends on dose.  The first aphorism implies the existence of agents or events potentially causing harm, but if insufficient to do so under the circumstances prevailing, actually confer benefit.  A simple example: We know that habitually consuming certain amounts of food increases our chances for a long healthy life &mdash; a beneficial effect &mdash; but that habitually consuming food in certain larger amounts, all other things equal, can result in numerous deleterious physiological/biochemical manifestations, some at least due to excessively-increasing the stores of body fat.  Some bad things, so to speak, arise from too much of good things. The example of the first aphorism applies also to the second aphorism. Thus the quantifiable in-principle biological phenomenon of ‘hormesis’ manifests itself.
+Biologists often begin their description of '''hormesis''' with the aphorism that '<i>what doesn’t kill you makes you stronger</i>' &mdash; implying an 'adaptation' response &mdash; or the aphorism that '<i>what makes something a medicine or a poison depends on dose</i>'. The first aphorism implies the existence of agents or events potentially causing harm, but if insufficient to do so under the circumstances prevailing, actually confer benefit.  The second aphorism emphasizes the dichotomous effects of the dose of a so-called medicine. The quantifiable, in-principle, biological phenomenon of ‘hormesis’ manifests itself in those ways.
-In their 2008 ''New Scientist'' article entitled, '''<font color=#660000>"Best in Small Doses"</font>''', hormesiologists Mark Mattson and Edward Calabrese write this applicable to the aphorism about adaptation:
+In their 2008 ''New Scientist'' article '''<font color=#660000>"Best in Small Doses"</font>''', hormesiologists Mark Mattson and Edward Calabrese write this applicable to the aphorism about adaptation:
-{|align="center" style="width:80%;"
-|
+<blockquote>
-<p style="color: #330066; font-size: 0.98em">'''<i>It describes the theory of hormesis - a process whereby organisms exposed to low levels of stress or toxins become more resistant to tougher challenges.</i>'''&nbsp; <ref name=mattsonns08>Mattson M, Calabrese E. (2008) [http://www.newscientist.com/channel/health/mg19926681.700-when-a-little-poison-is-good-for-you.html When a little poison is good for you.] ''New Scientist'' 9 August 2008. pp. 34-39.
+<p style="margin-left: 2.0%; margin-right: 6%; font-size: 1.0em; font-family: Trebuchet MS;">
-*'''<u>From the article:</u>'''&nbsp;Mark Mattson is chief of the laboratory of Neurosciences at the US National Institute on Aging and a professor of neurosciences at John Hopkins University in Baltimore, Maryland.  He is the most highly cited neuroscientist in the world.  Edward Calabrese is a professor of toxicology at the University of Massachusetts in Amherst.</ref>
+"It describes the theory of hormesis - a process whereby organisms exposed to low levels of stress or toxins become more resistant to tougher challenges."<ref name=mattsonns08>Mattson M, Calabrese E (2008) [http://www.newscientist.com/channel/health/mg19926681.700-when-a-little-poison-is-good-for-you.html When a little poison is good for you.] ''New Scientist'' 9 August 2008. pp. 34-39.
-</p>'''
+*<font face="Gill Sans MT">'''<u>From the article:</u>'''&nbsp; In 2008, Mark Mattson was chief of the laboratory of Neurosciences at the US National Institute on Aging and a professor of neurosciences at John Hopkins University in Baltimore, Maryland. He was then the most highly cited neuroscientist in the world. Edward Calabrese was a professor of toxicology at the University of Massachusetts in Amherst.</font></ref></p>
-|}
+</blockquote>
 [<i>New Scientist</i> editors announce the article as '''<font color=#660000>"When a little poison is good for you".</font>''']
-Biologists who specialize in the biochemical and physiological effects of toxic chemicals in living systems &mdash; [[Toxicology|toxicologists]] &mdash; use 'hormesis' to refer to the effects of certain (often environmental) chemicals, having definite toxic effects when exposed to the system above certain known doses, yet having beneficial effects when exposed to the system at doses lower than those that cause toxicity. <ref name=mattsonageing08>Mattson M. (2008) [http://dx.doi.org/10.1016/j.arr.2007.08.007 Hormesis defined.] ''Ageing Res.Rev.'' 7:1-7. PMID 18162444.
+Hormesis manifests itself not only in the circumstance of exposure to potentially toxic chemicals.  Any exposure or event that tends to stress the living system’s prevailing physiological status can potentially elicit a hormetic non-monotonic response.<ref name=mattsonageing08/> <font color=#151B54>'''"Examples include many chemicals, temperature, radiation, exercise, energy intake and others."'''</font> <ref name=mattsonageing08/>  Increasing the amount of physical activity by a more-or-less sedentary person, while it constitutes a stress on the cardiovascular and neuromuscular system long accustomed to relatively modest demands, may benefit the person’s general state of health. But an overenthusiastic convert to exercise may perform too much too quickly, resulting in injuries of many different kinds.
-*'''<u>Abstract:</u>'''&nbsp;Hormesis is a term used by toxicologists to refer to a biphasic dose-response to an environmental agent characterized by a low dose stimulation or beneficial effect and a high dose inhibitory or toxic effect. In the fields of biology and medicine hormesis is defined as an adaptive response of cells and organisms to a moderate (usually intermittent) stress. Examples include ischemic preconditioning, exercise, dietary energy restriction and exposures to low doses of certain phytochemicals. Recent findings have elucidated the cellular signaling pathways and molecular mechanisms that mediate hormetic responses which typically involve enzymes such as kinases and deacetylases, and transcription factors such as Nrf-2 and NF-kappaB. As a result, cells increase their production of cytoprotective and restorative proteins including growth factors, phase 2 and antioxidant enzymes, and protein chaperones. A better understanding of hormesis mechanisms at the cellular and molecular levels is leading to and to novel approaches for the prevention and treatment of many different diseases.</ref> They refer to the effect as “biphasic”: beneficial at 'low' doses, toxic at 'high' doses. 'Beneficial' may mean only that the agent stimulates a biochemical or physiological phenomenon at low doses and inhibits it at high doses, and does not necessarily mean beneficial in the strict positive sense of the word.
-Hormesis manifests itself not only in the circumstance of exposure to potentially toxic chemicals, as the example described above relating to gluttony illustrates.  Any exposure or event that tends to stress the living system’s prevailing physiological status can potentially elicit a hormetic biphasic response.<ref name=mattsonageing08/> <font color=#330066>'''"Examples include many chemicals, temperature, radiation, exercise, energy intake and others."'''</font> <ref name=mattsonageing08/>  Increasing the amount of physical activity by a more-or-less sedentary person, while it constitutes a stress on the cardiovascular and neuromuscular system long accustomed to relatively modest demands, may benefit the person’s general state of health.  But an overenthusiastic convert to exercise may perform too much too quickly, resulting in injuries of many different kinds.
+===''What doesn't kill you makes you stronger''===
+Mattson and Calabrese added another twist to hormesis when they it as '''<font color=#151B54>"a process whereby organisms exposed to low levels of <u>stress</u> or toxin become more resistant to tougher challenges"</font>'''<ref name=mattsonns08/> [emphasis added (as underline)] They write of the manifold defense molecules that the body actuates when a threat appears, that calling them to duty, so to speak, both counters the actuating threat <i>and</i> increases the body's ability to resist other threats. They exemplify that with the nerve cell toxicity produced by the high levels of the neurotransmitter, glutamate, that brain injury may release into the synapses connecting nerve cells, but which at lower levels can beneficially affect nerve cell survival and growth.  As another example of what they call '''<font color=#151B54>"hormetic stressors"</font>''', they write of the natural plant chemicals that act as 'natural' pesticides, protecting the plants against 'natural' pests.  In the amounts of those so-called phytochemicals that we consume with our fruit and vegetables, they actuate our body's responses to stress, but in high enough doses can cause toxic injury.
-Mattson and Calabrese add another twist to hormesis, defining it as '''<font color=#330066>"a process whereby organisms exposed to low levels of <u>stress</u> or toxin become more resistant to tougher challenges"</font>'''<ref name=mattson08/> [emphasis added (as underline)] They write of the manifold defense molecules that the body actuates when a threat appears, that calling them to duty, so to speak, both counters the actuating threat <i>and</i> increases the body's ability to resist other threats. They exemplify that with the nerve cell toxicity produced by the high levels of the neurotransmitter, glutamate, that brain injury may release into the synapses connecting nerve cells, but which at lower levels can beneficially affect nerve cell survival and growth.  As another example of what they call '''<font color=#330066>"hormetic stressors"</font>''', they write of the natural plant chemicals that act as 'natural' pesticides, protecting the plants against 'natural' pests.  In the amounts of those so-called phytochemicals that we consume with our fruit and vegetables, they actuate our body's responses to stress, but in high enough doses can cause toxic injury.
+Some biologists, including health science biologists, refer to an [[Adaptation|adaptive response]] of [[Cell (biology)|cells]] and [[Organism|organisms]] to '[[Stress|stress]]' of various categories, adaptation characterized by stronger resistance to the stressor when previously exposed to it at low levels.<ref name=crawford1994>Crawford DR, Davies KJA (1994) [http://www.ehponline.org/members/1994/Suppl-10/crawford-full.html Adaptive Response and Oxidative Stress.] <i> Environ Health Perspect</i> 102(Suppl 10) :25-28.
+*<b><u>Abstract:</u></b>The ability of a cell, tissue, or organism to better resist stress damage by prior exposure to a lesser amount of stress is known as adaptive response. It is observed in all organisms in response to a number of different cytotoxic agents. One of these agents, oxidative stress, is known to induce an adaptive response in bacteria that is accompanied by the induction of many proteins. De novo protein synthesis is required for adaptive response to oxidative and other types of stress, indicating that newly synthesized protective proteins are necessary for adaptation. Adaptive response to oxidative stress also has been observed in mammalian cells. Several studies suggest it is necessary to first preexpose mammalian cells to a somewhat toxic oxidative stress in order to observe significant resistance to a subsequent highly lethal dose of oxidant. Cross-resistance of oxidatively stressed cells to other toxic agents including - and X-irradiation, heat shock, aldehydes, [[heavy metal]]s, MNNG, N-ethylmaleimide, and heme also has been reported. Understanding oxidant adaptive response in more detail and identifying the protective proteins involved may prove to be of clinical benefit.</ref>
-‘Hormetic’ dose-response effects occur commonly and appear as a general biological phenomenon among numerous animal species, non-gender- or age-specific, among microorganisms as well. The response parameters &mdash; the effects displaying hormetic biphasicity &mdash; include growth, longevity, metabolic phenomena, disease incidence, cognitive functions, and immune responses. Exercise, caloric restriction, ethanol, caffeine, and various other stress factors, including radiation exposure, can also deliver hormetic responses.<ref name=mattsonns08/>&nbsp;<ref name=mattsonageing08/>&nbsp;<ref name=calabreseblain2005>Calabrese EJ, Blain R. (2005)  [http://dx.doi.org/10.1016/j.taap.2004.06.023 The occurrence of hormetic dose responses in the toxicological literature, the hormesis database: an overview. ''Toxicol. Appl. Pharmacol.'' 202:289-301. PMID 15667834.
+‘Hormetic’ dose-response effects  appear as a general biological phenomenon among numerous animal species, non-gender- or age-specific, among microorganisms as well. The response parameters &mdash; the effects displaying hormetic biphasicity &mdash; include growth, longevity, metabolic phenomena, disease incidence, cognitive functions, and immune responses. Exercise, caloric restriction, ethanol, caffeine, and various other stress factors, including radiation exposure, can also deliver hormetic responses.<ref name=mattsonns08/>&nbsp;<ref name=mattsonageing08/>&nbsp;<ref name=calabreseblain2005>Calabrese EJ, Blain R (2005) [http://dx.doi.org/10.1016/j.taap.2004.06.023 The occurrence of hormetic dose responses in the toxicological literature, the hormesis database: an overview. ''Toxicol. Appl. Pharmacol.'' 202:289-301 PMID 15667834.
-*'''<u>Abstract:</u>'''&nbsp;A relational retrieval database has been developed compiling toxicological studies assessing the occurrence of hormetic dose responses and their quantitative characteristics. This database permits an evaluation of these studies over numerous parameters, including study design and dose-response features and physical/chemical properties of the agents. The database contains approximately 5600 dose-response relationships satisfying evaluative criteria for hormesis across over approximately 900 agents from a broadly diversified spectrum of chemical classes and physical agents. The assessment reveals that hormetic dose-response relationships occur in males and females of numerous animal models in all principal age groups as well as across species displaying a broad range of differential susceptibilities to toxic agents. The biological models are extensive, including plants, viruses, bacteria, fungi, insects, fish, birds, rodents, and primates, including humans. The spectrum of endpoints displaying hormetic dose responses is also broad being inclusive of growth, longevity, numerous metabolic parameters, disease incidences (including cancer), various performance endpoints such as cognitive functions, immune responses among others. Quantitative features of the hormetic dose response reveal that the vast majority of cases display a maximum stimulatory response less than two-fold greater than the control while the width of the stimulatory response is typically less than 100-fold in dose range immediately contiguous with the toxicological NO(A)EL. The database also contains a quantitative evaluation component that differentiates among the various dose responses concerning the strength of the evidence supporting a hormetic conclusion based on study design features, magnitude of the stimulatory response, statistical significance, and reproducibility of findings.</ref> <ref name=calabresemed>Calabrese EJ. (2008)  Hormesis and medicine. ''Br. J Clin Pharmacol.'' PMID 18662293.
+*'''<u>Abstract:</u>'''&nbsp;A relational retrieval database has been developed compiling toxicological studies assessing the occurrence of hormetic dose responses and their quantitative characteristics. This database permits an evaluation of these studies over numerous parameters, including study design and dose-response features and physical/chemical properties of the agents. The database contains approximately 5600 dose-response relationships satisfying evaluative criteria for hormesis across over approximately 900 agents from a broadly diversified spectrum of chemical classes and physical agents. The assessment reveals that hormetic dose-response relationships occur in males and females of numerous animal models in all principal age groups as well as across species displaying a broad range of differential susceptibilities to toxic agents. The biological models are extensive, including plants, viruses, bacteria, fungi, insects, fish, birds, rodents, and primates, including humans. The spectrum of endpoints displaying hormetic dose responses is also broad being inclusive of growth, longevity, numerous metabolic parameters, disease incidences (including cancer), various performance endpoints such as cognitive functions, immune responses among others. Quantitative features of the hormetic dose response reveal that the vast majority of cases display a maximum stimulatory response less than two-fold greater than the control while the width of the stimulatory response is typically less than 100-fold in dose range immediately contiguous with the toxicological NO(A)EL. The database also contains a quantitative evaluation component that differentiates among the various dose responses concerning the strength of the evidence supporting a hormetic conclusion based on study design features, magnitude of the stimulatory response, statistical significance, and reproducibility of findings.</ref> <ref name=calabresemed>Calabrese EJ (2008) [http://dx.doi.org/10.1111/j.1365-2125.2008.03243.x Hormesis and medicine.] ''Br J Clin Pharmacol'' PMID 18662293.
-*'''<u>Abstract:</u>'''&nbsp;Evidence is presented which supports the conclusion that the hormetic dose-response model is the most common and fundamental in the biological and biomedical sciences, being highly generalizable across biological model, endpoint measured and chemical class and physical agent. The paper provides a broad spectrum of applications of the hormesis concept for clinical medicine including anxiety, seizure, memory, stroke, cancer chemotherapy, dermatological processes such as hair growth, osteoporosis, ocular diseases, including retinal detachment, statin effects on cardiovascular function and tumour development, benign prostate enlargement, male sexual behaviours/dysfunctions, and prion diseases.</ref> <ref name=stumpf06>Stumpf WE. (2006)  The dose makes the medicine. ''Drug Discov. Today'' 11:550-5. PMID 16713907.
+*'''<u>Abstract:</u>'''&nbsp;Evidence is presented which supports the conclusion that the hormetic dose-response model is the most common and fundamental in the biological and biomedical sciences, being highly generalizable across biological model, endpoint measured and chemical class and physical agent. The paper provides a broad spectrum of applications of the hormesis concept for clinical medicine including anxiety, seizure, memory, stroke, cancer chemotherapy, dermatological processes such as hair growth, osteoporosis, ocular diseases, including retinal detachment, statin effects on cardiovascular function and tumour development, benign prostate enlargement, male sexual behaviours/dysfunctions, and prion diseases.</ref> <ref name=stumpf06>Stumpf WE (2006)  The dose makes the medicine. ''Drug Discov Today'' 11:550-5 PMID 16713907.
 *'''<u>Abstract:</u>'''&nbsp;Dose and time considerations in the development and use of a drug are important for assessing actions and side effects, as well as predictions of safety and toxicity. This article deals with epistemological aspects of dose selection by probing into the linguistic and cultural roots for the measure of medicine mediated by the medical doctor. Because toxicity is related to dose, historic and recent views suggest that less can be more. At low, medium and high dose levels, effects can differ not only quantitatively but also qualitatively. Dose-related target activation and recognition of enantiodromic thresholds between beneficial and toxic effects require elucidation of underlying events. Such studies, including hormesis and microdosing, call for extended ADME procedures with high-resolution methods in addition to the current low-resolution approaches. Improved information of drug logistics and target pharmacokinetics enables effective drug selection, dose determination and prediction. It also allows considerations of systems biology [i.e. integral (gestalt) pharmacology] exemplified by the drug homunculus, as in the case of vitamin D, that might lead to new paradigms and drug design.</ref>
-British hormesiologist A. R. D. Stebbing explains the hormetic effect as an evolved biological adaptation that prepares organisms to resist the toxic effects of a range of different environmental stressors,<ref name=stebbing1987>Stebbing AR. (1987) [http://www.ncbi.nlm.nih.gov/pubmed/2883157?dopt=Citation Growth hormesis: a by-product of control.] <i>Health Phys</i> 52:543-7.
+British hormesiologist A. R. D. Stebbing explains the hormetic effect as an evolved biological adaptation that prepares organisms to resist the toxic effects of a range of different environmental stressors,<ref name=stebbing1987>Stebbing AR. (1987) [http://www.ncbi.nlm.nih.gov/pubmed/2883157?dopt=Citation Growth hormesis: a by-product of control.] <i>Health Phys</i> 52:543-7
 *<b><u>Abstract:</u></b> Data from experiments, in which colonies of a hydroid, Laomedea flexuosa, were exposed to a range of Cu2+ concentrations and a marine yeast, Rhodotorula rubra, was exposed to a range of Cd2+ concentrations, not only exhibit hormesis, but also suggest how its occurrence in growth experiments might be explained. When growth data are considered as normalized specific rates against a time base, their oscillatory form indicates the output of a growth regulatory mechanism whose behaviour can be used to interpret the typical concentration-response curve exhibiting hormesis. Advantages may be conferred upon organisms whose growth control mechanisms overcorrect in response to low levels of inhibitory loading by toxic agents (stimulus), while at higher concentrations it is the overloading of such control mechanisms that results in the threshold in concentration-response curves (inhibition). It is suggested that if different examples of hormesis share a common explanation, it lies in the behaviour of homeostatic and homeorhetic feedback mechanisms, which respond to perturbation non-specifically and may overcorrect for adaptive reasons to low levels of inhibitory challenge.</ref> <ref name=stebbing2000>Stebbing AR. (2000) [http://www.ncbi.nlm.nih.gov/pubmed/2883157?dopt=Citation Hormesis: interpreting the beta-curve using control theory.] <i>J Appl Toxicol</i> 20:93-101.
 *'''<u>Abstract:</u>''' Data from experiments exposing colonial hydroids to toxic growth inhibitors have provided evidence of growth control mechanisms that respond adaptively to counter toxic inhibition. Analysis of growth data and the development of simulation models provide an interpretation of both alpha- and beta-curves. The hypothesis also suggests that hormesis is related to adaptation by growth control mechanisms that confer tolerance to subsequent exposure.</ref> comparable to the evolved biological adaptation referred to as '[[Homeostasis (Biology)|homeostasis]]':
-{|align="center" style="width:80%;"
+<blockquote>
-|
+<p style="margin-left: 2.0%; margin-right: 6%; font-size: 1.0em; font-family: Trebuchet MS;">[[Occam's razor|Ockham’s Razor]] leads one to look for the most economical hypothesis, which for hormesis is more likely to depend on some common property of the organisms than the toxic agents to which they are exposed. The range of examples suggests that hormesis is not so much an effect of the specific agents that induce it, but an adaptive response to the inhibitory effect they share, because it is improbable that any toxicant-specific interpretation could account for the widespread occurrence of the b[eta]-curve [the biphasic hormetic curve]. The idea that hormesis is due to a biological response is also attractive in an evolutionary sense, because organisms are thus pre-adapted to toxic inhibition whatever the specific cause.<ref name=stebbing2000/></p>
-<p style="color: #151B54; font-size: 0.98em">'''<i>Ockam’s Razor leads one to look for the most economical hypothesis, which for hormesis is more likely to depend on some common property of the organisms than the toxic agents to which they are exposed. The range of examples suggests that hormesis is not so much an effect of the specific agents that induce it, but an adaptive response to the inhibitory effect they share, because it is improbable that any toxicant-specific interpretation could account for the widespread occurrence of the b[eta]-curve [the biphasic hormetic curve]. The idea that hormesis is due to a biological response is also attractive in an evolutionary sense, because organisms are thus pre-adapted to toxic inhibition whatever the specific cause.</i>'''&nbsp;<ref name=stebbing2000/></p>'''
+</blockquote>
+At low doses of stressor, the evolved adaptive, or homeostatic, mechanism 'overcompensates', bringing about the stimulatory or beneficial effect, the 'overcompensation' feature itself an evolved adaptive mechanism that strengthens with exposure to the stressor, accounting for '''<i><font color=#151B54>....a process whereby organisms exposed to low levels of stress or toxins become more resistant to tougher challenges.</font></i>'''<ref name=mattsonns08/>
+==Proposed mechanisms for hormesis==
+Holding ref:<ref name=zhang2008>Zhang Q, Pi J, Jarabek AM, Clewell III HJ, Anderson ME. (2008) [http://dx.doi.org/10.2203/dose-response.07-028.Zhang Hormesis and adaptive cellular control systems.] ''Dose-Response'' 6:196-208.
+*<b><u>Abstract:</u></b>&nbsp;Hormetic dose response occurs for many endpoints associated with exposures of biological organisms to environmental stressors. Cell-based U- or inverted U-shaped responses may derive from common processes involved in activation of adaptive responses required to protect cells from stressful environments. These adaptive pathways extend the region of cellular homeostasis and are protective against ultimate cell, organ, and system toxicity. However, the activation of stress responses carries a significant energetic cost to the cell, leading to alterations of a variety of basal cellular functions in adapted or stressed cells. This tradeoff of resources between the unstressed and adapted states may lead to U-or inverted U-shaped dose response curves for some precursor endpoints. We examine this general hypothesis with chlorine, a prototype oxidative stressor, using a combination of cellular studies with gene expression analysis of response pathways and with computational modeling of activation of control networks. Discrete cellular states are expected as a function of exposure concentration and duration. These cellular states include normal functioning state, adaptive and stressed states at mild to intermediate exposures, and overt toxicity in the presence of an overwhelming concentration of stressors. These transitions can be used to refine default risk assessment practices that do not currently accommodate adaptive responses.</ref> <ref name=stebbing1998>Stebbing AR. (1998) A theory for growth hormesis. Mutat Res 403: 249-58. PMID 9726025.
+*<b><u>Excerpt:</u></b>&nbsp;The hypothesis tested therefore was that hormesis is a consequence of an adaptive response common to biological systems to the inhibitory effect that the different agents have in common at higher concentrations.</ref> <ref name=calabresecrittox01>Calabrese EJ. (2001) [http://dx.doi.org/10.1080/20014091111749 Overcompensation stimulation: A mechanism for hormetic effects.] ''Crit Rev Toxicol'' 31: 425-70.
+*<b><u>Abstract:</u></b>&nbsp;Whether hormetic responses result from a direct or an overcompensation type of stimulatory response has been an unresolved and contentious issue in both radiation and chemical toxicology. The goal of the present article is to identify numerous examples of overcompensation stimulation in the biological/biomedical literature and to evaluate their descriptive and quantitative features. The findings provide support for the hypothesis that hormetic dose-response relationships from a broad array of biological models can occur after an initial disruption in homeostasis. The finding also demonstrates the significant role of temporal factors in the assessment of dose response relationships. </ref>
+==Controversial issues==
+{|align="right" cellpadding="10" style="background:lightgray; width:35%; border: 1px solid #aaa; margin:20px; font-size: 93%; font-family: Gill Sans MT;"
+| The concept of hormesis has not escaped its share of controversy. Some researchers question whether scientists have developed adequate methods for distinguishing when a beneficial effect ends and a toxic one begins. The exact threshold for when a toxic reaction starts may vary by individual, making it difficult to use hormesis as a basis for drug therapies. Skepticism arises, too, when the basic concept is extended to ionizing radiation, such as x-rays, for which low doses have been shown to have beneficial effects on healthy lab animals. Various scientific advisory bodies, however, have rejected radiation as unsafe for humans even at the lowest levels.
+|-
+|&nbsp;&nbsp;&mdash; By Mark P. Mattson, Jun 16, 2015, Scientific American Magazine
 |}
-At low doses of stressor, the evolved adaptive, or homeostatic, mechanism 'overcompensates', bringing about the stimulatory or beneficial effect, the 'overcompensation' feature itself an evolved adaptive mechanism that strengthens with exposure to the stressor, accounting for '''<i><font color=#151B54>....a process whereby organisms exposed to low levels of stress or toxins become more resistant to tougher challenges.</font></i>'''&nbsp;<ref name=mattsonns08/>
+Scientists have not universally accepted hormesis, though the discussion remains active. <ref>[http://www.belleonline.com/newsletters/volume6/vol6-1.html LOW DOSE LINEARITY: THE RULE OR THE EXCEPTION.] BELLE Newsletter Vol 6, No. 1, March 1997.
+*'''<u>From the Introduction:</u>''' A recently published paper by Martha Crawford and Richard Wilson entitled "Low-Dose Linearity: The Rule or the Exception? " in the journal Human and Ecological Risk Assessment, Vol. 2, No. 2, 1996 argued that low dose linearity of the dose response curve might be the rule rather than the exception. While the assumption of low dose linearity has been widely accepted in concept and implemented in U.S. federal risk assessment practices for radiation and chemical carcinogens, it has not been believed to apply to non-carcinogens that have been accepted without controversy as having thresholds below which no adverse effects would be expected. However, Crawford and Wilson contend that the concept of low dose linearity is broadly generalizable and should apply to non-carcinogens as well. Their article, which urges a reconsideration of how background response is considered in risk assessment, challenges not only the vast array of current assertions that low dose linearity is no longer appropriate for low dose cancer risk assessment but suggests that non-carcinogen risk assessment practices may need to be reconsidered as well…While the BELLE initiative has focused on an assessment of the wide possible range of dose response relationships in the low dose zone, the BELLE Newsletter has published a series of papers that have challenged the notion of low dose linearity based on theoretical foundation, as well as experimental/epidemiological and mechanistic studies. Thus, given the potentially controversial, yet substantial, nature of the Crawford and Wilson paper, it was felt that there should be a broad discussion of this paper since it is at the heart of critical issues in the risk assessment process. Consequently, Dr. Richard Wilson was contacted and asked to prepare a shortened form (e.g., 10 pages down from over 30 pages) of the original article. He also agreed to consider and respond to the comments of a number of external experts that would be invited to offer independent commentary on this paper. The reviewers were sent both the original (longer) version and the shortened form which is now published in the Newsletter. We trust that you will find this discussion both challenging and enlightening.</ref>
+Thayer et al. write:<ref name=thayer2006>Thayer KA, Melnick R, Huff J, Burns K, Davis D. (2006) [http://www.ehponline.org/docs/2006/9717/letter.html Hormesis: A New Religion?] <i>Environmental Health Perspectives</i> Nov;114(11):A632-3.  PMID 17107829 PMCID: PMC 1665404.</ref>
+<blockquote>
+<p style="margin-left: 2.0%; margin-right: 6%; font-size: 1.0em; font-family: Trebuchet MS;">Cook and Calabrese (2006)<ref name=cook2006>Cook R, Calabrese EJ. (2006) [http://dx.doi.org/10.1289/ehp.8606 The importance of hormesis to public health.] <i>Environ Health Perspect</i> 114:1631–1635;  [Online 10 July 2006].</ref>  make inaccurate claims about our perspective on hormesis (Thayer et al. 2005).<ref name=thayer2005>Thayer KA, Melnick R, Burns K, Davis D, Huff J. (2005) Fundamental flaws of hormesis for public health decisions. <i>Environ Health Perspect</i> 113:1271-1276.</ref> They define hormesis as "low-dose stimulation and high-dose inhibition," declaring "beneficial/harmful effects should not be part of the definition, but reserved to subsequent evaluation. . . ." Yet, they advocate higher permissible environmental levels of hazardous agents based on purported health benefits. Cook and Calabrese promote changing the way carcinogens are regulated to accommodate hormesis, recognizing that this "would result in cancer risk assessment values about 100- to 200-fold higher than currently employed" (Calabrese and Cook 2005).<ref name=calabresecook2005>Calabrese EJ, Cook RR. 2005. Hormesis: how it could affect the risk assessment process. <i>Hum Exp Toxicol</i> 24(5):265-270.</ref>  Previously, Calabrese and Baldwin (2003a)<ref name=calabresebaldwin2003a>Calabrese EJ, Baldwin LA. (2003) Hormesis: the dose-response revolution. <i>Annu Rev Pharmacol Toxicol</i> 43:175-197.</ref> stated, "agencies will need to accept the possibility (actually, the likelihood) that toxic substances, even the most highly toxic (e.g., cadmium, lead, mercury, dioxin, PCBs, etc.) can cause beneficial effects at low doses."</p>
+</blockquote>
+Subsequently, however, Calabrese, the leading explicator and articulator of the hormesis concept, clarifies his position, writing in 2008:
-Scientists have not universally accepted hormesis, though the discussion remains active. <ref>[http://www.belleonline.com/newsletters/volume6/vol6-1.html LOW DOSE LINEARITY: THE RULE OR THE EXCEPTION.] BELLE Newsletter Vol 6, No. 1, March 1997.
+<blockquote>
-*'''<u>From the Introduction:</u>''' A recently published paper by Martha Crawford and Richard Wilson entitled "Low-Dose Linearity: The Rule or the Exception? " in the journal Human and Ecological Risk Assessment, Vol. 2, No. 2, 1996 argued that low dose linearity of the dose response curve might be the rule rather than the exception. While the assumption of low dose linearity has been widely accepted in concept and implemented in U.S. federal risk assessment practices for radiation and chemical carcinogens, it has not been believed to apply to non-carcinogens that have been accepted without controversy as having thresholds below which no adverse effects would be expected. However, Crawford and Wilson contend that the concept of low dose linearity is broadly generalizable and should apply to non-carcinogens as well. Their article, which urges a reconsideration of how background response is considered in risk assessment, challenges not only the vast array of current assertions that low dose linearity is no longer appropriate for low dose cancer risk assessment but suggests that non-carcinogen risk assessment practices may need to be reconsidered as well…While the BELLE initiative has focused on an assessment of the wide possible range of dose response relationships in the low dose zone, the BELLE Newsletter has published a series of papers that have challenged the notion of low dose linearity based on theoretical foundation, as well as experimental/epidemiological and mechanistic studies. Thus, given the potentially controversial, yet substantial, nature of the Crawford and Wilson paper, it was felt that there should be a broad discussion of this paper since it is at the heart of critical issues in the risk assessment process. Consequently, Dr. Richard Wilson was contacted and asked to prepare a shortened form (e.g., 10 pages down from over 30 pages) of the original article. He also agreed to consider and respond to the comments of a number of external experts that would be invited to offer independent commentary on this paper. The reviewers were sent both the original (longer) version and the shortened form which is now published in the Newsletter. We trust that you will find this discussion both challenging and enlightening.</ref>
+<p style="margin-left: 2.0%; margin-right: 6%; font-size: 1.0em; font-family: Trebuchet MS;">The hormetic dose–response may be reliably described as a being a stimulation in the low dose zone, followed by an inhibitory response at higher doses....the stimulatory zone [dose range where stimulation occurs] defines the therapeutic window. It may also define an adverse effect window, as in the case when low doses of anti-tumour drugs stimulate tumour growth [citation given]. It is also important to recognize that the hormetic stimulatory zone is graphically contiguous with the pharmacologic/toxicologic threshold. This indicates that there is the distinct possibility of a desired therapeutic dose being a toxic dose to some individuals due to extensive interindividual variation.<ref name=calabresemed/></p>
+</blockquote>
-==History of hormesis==
+==History of hormesis concept==
 Hormesiologist A.R.D. Stebbing offers a succinct account of the history of the phenomenon and concept of hormesis: <ref name=stebbinghx> A.R.D. Stebbing, Ph.D. (1997) [http://www.belleonline.com/newsletters/volume6/vol6-2.html A Theory for Growth Hormesis.] BELLE Newsletter Vol 6, No. 1, September 1997.</ref> <ref>'''<u>Note:</u>''' The editors divided this excerpt of Stebbing into paragraphs for easier reading.</ref>
-{|align="center" style="width:85%;"
+<blockquote>
-|
+<p style="margin-left: 2.0%; margin-right: 6%; font-size: 1.0em; font-family: Trebuchet MS;">Examples of hormesis gathered from the literature show that hormesis has a long and interesting history. The concentration-response curves for quite a wide range of toxic agents followed a typical pattern, termed the betacurve (Townsend & Luckey, 1960). The occurrence of such curves in toxicological experiments was discovered independently and named on several occasions. Over a century ago Schultz's experiments (1888) showed that many chemical agents had the effect of stimulating the growth and respiration of yeast. The phenomenon became known as the Arndt-Schultz Law and was widely referred to in the pharmacological literature for over 30 years and became one of the scientific principles on which homeopathy is based. However, the potency of homeopathic medicines is believed to increase with their dilution over many orders of magnitude, rather than restricted to a narrow range of concentrations like hormesis.<ref name=stebbinghx/></p>
-<p style="color: #330066; font-size: 0.98em">'''<i>Examples of hormesis gathered from the literature show that hormesis has a long and interesting history. The concentration-response curves for quite a wide range of toxic agents followed a typical pattern, termed the betacurve (Townsend & Luckey, 1960). The occurrence of such curves in toxicological experiments was discovered independently and named on several occasions. Over a century ago Schultz's experiments (1888) showed that many chemical agents had the effect of stimulating the growth and respiration of yeast. The phenomenon became known as the Arndt-Schultz Law and was widely referred to in the pharmacological literature for over 30 years and became one of the scientific principles on which homeopathy is based. However, the potency of homeopathic medicines is believed to increase with their dilution over many orders of magnitude, rather than restricted to a narrow range of concentrations like hormesis.</i>'''&nbsp;<ref name=stebbinghx/></p>'''
+</blockquote>
-|
-|}
+<blockquote>
+<p style="margin-left: 2.0%; margin-right: 6%; font-size: 1.0em; font-family: Trebuchet MS;">Hueppe (1896) at about that time made similar observations on bacteria, apparently unaware of Schultz's experiments. His generalization became known as Hueppe's Rule.<ref name=stebbinghx/></p>
+</blockquote>
+<blockquote>
+<p style="margin-left: 2.0%; margin-right: 6%; font-size: 1.0em; font-family: Trebuchet MS;">Long before them both, the German alchemist and physician Theophrastus Bombastus von Hohenheim ((1493-1541), who coined for himself the name *Paracelsus*, had recognized with respect to the medical use of small amounts of toxic chemicals that their efficacy depended principally on the dose. Such ideas are perhaps more easily accepted nowadays, when it is in the experience of most to use the stimulatory effects of alcohol, caffeine or nicotine, all of which are toxic at high concentrations.<ref name=stebbinghx/></p>
+</blockquote>
+<blockquote>
+<p style="margin-left: 2.0%; margin-right: 6%; font-size: 1.0em; font-family: Trebuchet MS;">Much later Southam and Ehrlich (1943) studied the effect of a natural antibiotic in cedar wood that inhibits the growth of wood-decaying fungi. They found that subinhibitory concentrations of the antibiotic had the reverse effect and stimulated fungal growth. The term "hormesis" was coined to describe it; which we still use today. Some of the observations have an interesting origin. In the later stages of World War II, when supplies of penicillin were in such short supply, work of Miller et al. (1945) explained why reducing the dose to make short supplies of the new drug go further sometimes had the reverse of the desired effect. At low doses penicillin actually stimulated the growth of Staphylococcus . In other examples closer to my own field, experiments with oyster lar vae showed that low levels of many pesticides actually stimulated growth in the same way (Davis & Hidu, 1969). The greatest authority in the field of hormesis is Dr Thomas Luckey, whose early work was on the use of antibiotics as dietary supplements to stimulate growth in poultry (Luckey, 1956)<ref name=stebbinghx/></p>
+</blockquote>
+References cited by Professor Stebbing in the above excerpt:
+Townsen and Luckey 1960<ref name=townsend1960>Townsend, J.F. & Luckey, T.D., 1960. Hormoligosis in pharmacology. J. Am. Med. Assoc., 173: 44-48. Waddington, C.H., 1977. Tools for Thought.  London: Jonathan Cape. </ref> |
+Schultze 1888<ref name=schultz1888>Schultz, H., 1888. Ueber Hefegifte. Pflugers Archiv fur die gesamte Physiologie des Menschen und der Tierre, 42, 517-541. </ref> |
+Hueppe 1896<ref name=hueppe1896>Hueppe, F., 1896. The Principles of Bacteriology. Chicago Open Court. </ref> |
+Southam and Ehrlich 1943<ref name=southam1943>Southam, C.M. & Ehrlich, J., 1943. Effects of extracts western red cedar heartwood on certain wood-decaying fungi in culture. Phytopathology, 33: 5517-524. </ref> |
+Miller et al. 1945<ref name=miller1945>Miller WS, Green CA, Kitchen H. (1945) [http://dx.doi.org/10.1038/155210a0 Biphasic action of penicillin and other similar sulphonamides.] Nature, Lond., 155, 210-211.
+*'''<u>First paragraph:</u>''' SUBSTANCES generally acknowledged as being toxic to cells may have an opposite effect in higher dilution. This biphasic action inhibition in high concentrations and stimulation in low concentrations has been observed with a wide variety of substances, including narcotics, cyanide, pyrithiaminel and sulphonamides [citation given]. There is ample evidence that low concentrations of the last group stimulate bacterial growth; and it would appear that the period of active proliferation, which frequently precedes bacteriostasis by sulphonamides in higher concentrations, is a manifestation of the same phenomenon. We here report what appears to be an expression of the same effect occurring with penicillin.</ref> |
+Davis and Hidu 1969<ref name=davis1969>Davis, H.C. & Hidu, H., 1969. Effects of pesticides on embryonic development of clams and oysters and on survival and growth of the larvae. Fish Bull. Fish Wildl. Serv. U.S., 67: 393-404. </ref> |
+Luckey 1956<ref name=luckey1956>Luckey, T.D., 1956. Mode of action of antibiotics evidence from germ - free birds. In: 1st International Conference on the Use of Antibiotics in Agriculture. p135. National Academy of Sciences, Washington DC.</ref>
+==Definitional considerations==
+Hormesiologists Edward J. Calabrese and Linda A. Baldwin provide an introduction to definitional considerations with the abstract of their paper, ''Defining Hormesis'' <ref name=calabresebellefeb02>Edward J. Calabrese and Linda A. Baldwin. (2002) PART 2: PROPOSING A DEFINITION OF HORMESIS: DEFINING HORMESIS. BELLE Newsletter. A Publication of the Northeast Regional Environmental Public Health Center, University of Massachusetts, School of Public Health, Amherst, MA 01003. Vol. 10, No. 2, February 2002, ISSN 1092-4736. [http://www.belleonline.com/newsletters.htm Full-Text Online]</ref> upon which the nuances of the concept permit explication:
+<blockquote>
+<p style="margin-left: 2.0%; margin-right: 6%; font-size: 1.0em; font-family: Trebuchet MS;">Much confusion surrounds the concept of hormesis and what its biological meaning represents. This paper provides a definition of hormesis that addresses its historical foundations, quantitative features, and underlying evolutionary- and toxicologically-based mechanistic strategies.<br>
+<br>
+Hormesis should be considered an adaptive response characterized by biphasic dose responses of generally similar quantitative features with respect to amplitude and range of the stimulatory response that are either directly induced or the result of compensatory biological processes following an initial disruption in homeostasis.<br>
+<br>
+Given the limited magnitude of the stimulatory response (i.e., usually 30-60% greater than controls at maximum), heightened study design and replication requirements are often necessary to ensure reliable judgments on causality. Even though hormesis is considered an adaptive response, the issue of beneficial/ harmful effects should not be part of the definition of hormesis, but reserved to a subsequent evaluation of the biological and ecological context of the response.<ref name=calabresebellefeb02/></p>
+</blockquote>
+More recently, Vaiserman writes:
+<blockquote>
+<p style="margin-left: 2.0%; margin-right: 6%; font-size: 1.0em; font-family: Trebuchet MS;">Hormesis (the shape of the dose–response patterns when low doses elicit an adaptive response of the cell/organism...<ref name=vaiserman2010>Vaiserman AM. (2010) [http://dx.doi.org/10.2203/dose-response.09-014.Vaiserman Hormesis, adaptive epigenetic reorganization, and implications for human health and longevity.] ''Dose Response'' 2010;8:16-21.
+<b>From Abstract:</b> Evidence supporting that hormetic-like effects may be the result of a generalized whole-organism adaptive epigenetic response is reviewed. Specific hormesis-inducing interventions during development would allow to achieve an optimal balance between activation and repression of various genes and thus to prevent age-related degenerative diseases and slow aging.</ref></p>
+</blockquote>
+==Mitochondrial hormesis (mitohormesis)==
+Holding refs:
+<ref name=schmeisser2011>Schmeisser S, Zarse K, Ristow M. (2011) [http://dx.doi.org/10.1055/s-0031-1286308 Lonidamine extends lifespan of adult Caenorhabditis elegans by increasing the formation of mitochondrial reactive oxygen species]. ''Horm Metab Res'' 43:687-92.
+*<font face="Gill Sans MT">"The aim of the study was to test whether pharmaceutical concentrations of the glycolytic inhibitor lonidamine are capable of extending lifespan in a nematodal model organism for aging processes, the roundworm Caenorhabditis elegans...Lonidamine significantly extends both median and maximum lifespan of C. elegans...Moreover, the compound increases paraquat stress resistance, and promotes mitochondrial respiration, culminating in increased formation of reactive oxygen species (ROS). Extension of lifespan requires activation of pmk-1, an orthologue of p38 MAP kinase, and is abolished by co-application of an antioxidant, indicating that increased ROS formation is required for the extension of lifespan by lonidamine. Consistent with the concept of mitohormesis, lonidamine is capable of promoting longevity in a pmk-1 sensitive manner by increasing formation of ROS."</font></ref>
+<ref name=ristow2011>Ristow M, Schmeisser S. (2011) [http://dx.doi.org/10.1016/j.freeradbiomed.2011.05.010 Extending life span by increasing oxidative stress]. ''Free Radic Biol Med'' 51:327-36.
+*<font face="Gill Sans MT">"This review aims to summarize published evidence that several longevity-promoting interventions may converge by causing an activation of mitochondrial oxygen consumption to promote increased formation of reactive oxygen species (ROS). These serve as molecular signals to exert downstream effects to ultimately induce endogenous defense mechanisms culminating in increased stress resistance and longevity, an adaptive response more specifically named mitochondrial hormesis or mitohormesis. Consistently, we here summarize findings that antioxidant supplements that prevent these ROS signals interfere with the health-promoting and life-span-extending capabilities of calorie restriction and physical exercise. Taken together and consistent with ample published evidence, the findings summarized here question Harman's Free Radical Theory of Aging and rather suggest that ROS act as essential signaling molecules to promote metabolic health and longevity."</font></ref>
+==Hormesis and plant biology==
+Numerous studies indicate that plants exhibit hormetic dose-response effects to cytotoxic stressors quantitatively similar to those occurring in animals.<ref name=calabreseplantbiol>Calabrese EJ, Blain RB. (2009) [http://dx.doi.org/10.1016/j.envpol.2008.07.028 Hormesis and plant biology]. ''Environ Pollut'' 157:42-48.</ref> Plant biologists study how hormesis in plants might be exploited for plant growth enhancement and for soil remediation.<ref name=calabreseplantbiol/>
+==Xenohormesis==
+<b>Xenohormesis</b>, a subdiscipline of hormesis, refers to the phenomenon of adaptive cellular responses of humans and other mammals to the typically low-dose amounts of plant toxins consumed with their ordinary diets &mdash; adaptive responses that confer resistance to stressors and other benefits to health.<ref name=surhxeno1>Young-Joon Surh. (2011) [http://dx.doi.org/10.1111/j.1749-6632.2011.06097.x Xenohormesis mechanisms underlying chemopreventive effects of some dietary phytochemicals]. ''Ann. N.Y. Acad. Sci.'' 1229 :1–6.</ref>&nbsp; <ref name=horwitzxeno1>Konrad T. Howitz, David A. Sinclair. (2008) [http://dx.doi.org/10.1016/j.cell.2008.04.019  Xenohormesis: Sensing the Chemical Cues of Other Species]. ''Cell'' 133:387-391</ref>
+Plants produce toxins, called [[phytoalexins]], that protect them from environmental stressors, including a variety of injurious organisms, for example insects.  The low-doses that humans receive from consuming plant foods serve as mild stressors, which the body uses to a health advantage.
+What doesn’t kill you makes you stronger.  Dose determines whether a substance acts as a poison or a tonic.
+Ames and colleagues report:
+<blockquote>
+<p style="margin-left: 2%; margin-right: 6%; font-size: 1.0em; font-family: Gill Sans MT, Trebuchet MS;">
+We calculate that 99.99% (by weight) of the pesticides in the American diet are chemicals that plants produce to defend themselves. Only 52 natural pesticides have been tested in high-dose animal cancer tests, and about half (27) are rodent carcinogens; these 27 are shown to be present in many common foods. We conclude that natural and synthetic chemicals are equally likely to be positive in animal cancer tests. We also conclude that at the low doses of most human exposures the comparative hazards of synthetic pesticide residues are insignificant. <ref name=amesxeno1>Ames BN, Profet M, Gold LS. (1990) [http://www.jstor.org/stable/2355314 Dietary pesticides (99.99% all natural)]. ''Proc. Natl. Acad. Sci. USA'' 87:7777-7781.</ref></p>
+</blockquote>
-{|align="center" style="width:85%;"
+If low-dose intermittent consumption of chemicals that induce cancer at high-dose behave hormetically, the word “insignificant” in the quote understates the case.
-|
-<p style="color: #330066; font-size: 0.98em">'''<i>Hueppe (1896) at about that time made similar observations on bacteria, apparently unaware of Schultz's experiments. His generalization became known as Hueppe's Rule.</i>'''&nbsp;<ref name=stebbinghx/></p>'''
-|
-|}
-{|align="center" style="width:85%;"
+Xenohormesis more broadly refers to the adaptive responses to the sensing, from other species, of chemical clues about potential environmental dangers, an evolved preconditioning function, predicting the future, serving survival advantage given the inevitable inimical influences in Earth’s bio- and geospheres.<ref name=horwitzxeno1/>
-|
-<p style="color: #330066; font-size: 0.98em">'''<i>Long before them both, the German alchemist and physician Theophrastus Bombastus von Hohenheim ((1493-1541), who coined for himself the name *Paracelsus*, had recognized with respect to the medical use of small amounts of toxic chemicals that their efficacy depended principally on the dose. Such ideas are perhaps more easily accepted nowadays, when it is in the experience of most to use the stimulatory effects of alcohol, caffeine or nicotine, all of which are toxic at high concentrations.</i>'''&nbsp;<ref name=stebbinghx/></p>'''
-|
-|}
-{|align="center" style="width:85%;"
+==Hormesis vs. homeopathy==
-|
+Menachem Oberbaum, Noah Samuels, and Shepherd Roee Singer, of The Center for Integrative Complementary Medicine, Shaare Zedek Medical Center, Jerusalem, Israel, argue that "hormesis is not [[Homeopathy|homeopathy]]", stating, among other differences, that:
-<p style="color: #330066; font-size: 0.98em">'''<i>Much later Southam and Ehrlich (1943) studied the effect of a natural antibiotic in cedar wood that inhibits the growth of wood-decaying fungi. They found that subinhibitory concentrations of the antibiotic had the reverse effect and stimulated fungal growth. The term "hormesis" was coined to describe it; which we still use today. Some of the observations have an interesting origin. In the later stages of World War II, when supplies of penicillin were in such short supply, work of Miller et al. (1945) explained why reducing the dose to make short supplies of the new drug go further sometimes had the reverse of the desired effect. At low doses penicillin actually stimulated the growth of Staphylococcus . In other examples closer to my own field, experiments with oyster lar vae showed that low levels of many pesticides actually stimulated growth in the same way (Davis & Hidu, 1969). The greatest authority in the field of hormesis is Dr Thomas Luckey, whose early work was on the use of antibiotics as dietary supplements to stimulate growth in poultry (Luckey, 1956). </i>'''&nbsp;<ref name=stebbinghx/></p>'''
-|
-|}
-References cited by Professor Stebbing in the above excerpt: <ref name=townsend1960>Townsend, J.F. & Luckey, T.D., 1960. Hormoligosis in pharmacology. J. Am. Med. Assoc., 173: 44-48. Waddington, C.H., 1977. Tools for Thought.  London: Jonathan Cape. </ref> <ref name=schultz1888>Schultz, H., 1888. Ueber Hefegifte. Pflugers Archiv fur die gesamte Physiologie des Menschen und der Tierre, 42, 517-541. </ref> <ref name=hueppe1896>Hueppe, F., 1896. The Principles of Bacteriology. Chicago Open Court. </ref> <ref name=southam1943>Southam, C.M. & Ehrlich, J., 1943. Effects of extracts western red cedar heartwood on certain wood-decaying fungi in culture. Phytopathology, 33: 5517-524. </ref> <ref name=miller1945>M i l l e r, W.S., Green, C.A. & Kitchen, H., 1945. Biphasic action of penicillin and other similiar sulphonamides. Nature , Lond., 155, 210-211. </ref> <ref name=davis1969>Davis, H.C. & Hidu, H., 1969. Effects of pesticides on embryonic development of clams and oysters and on survival and growth of the larvae. Fish Bull. Fish Wildl. Serv. U.S., 67: 393-404. </ref> <ref name=luckey1956>Luckey, T.D., 1956. Mode of action of antibiotics evidence from germ - free birds. In: 1st International Conference on the Use of Antibiotics in Agriculture. p135. National Academy of Sciences, Washington DC.</ref>
+<blockquote>
+<p style="margin-left: 2.0%; margin-right: 6%; font-size: 1.0em; font-family: Trebuchet MS;">Whereas hormetic (chemical) responses are induced by small but measurable concentrations (above Avogardo’s number), homeopathic concentrations are often far below this. The use of a remedy with a "concentration" of 10<sup>-400</sup> of the stem solution is common practice in classic homeopathy....Hormetic substances do not require any special preparation. Homeopathic remedies, in contrast, require a lengthy and exacting process before they are ready for administration.<ref>Oberbaum M, Samuels N, Singer SR. (2005) [http://dx.doi.org/10.1016/j.taap.2005.05.011 Hormesis is not homeopathy.] ''Toxicology and Applied Pharmacology'' 206:365– 366.</ref></p>
+</blockquote>
-==References and notes cited in text==
+==References and notes cited in text as superscripts==
-{|cellpadding=10 align=center style="width:85%; border: solid 1px #4682b4; background:lightblue"
+{|cellpadding=10 align=center style="width:85%; border: solid 1px #4682b4; background:lightyellow"
 |
-''Many citations to articles listed here include links to full-text &mdash; in font-color <font color="blue"> blue</font>.  Accessing full-text may require personal or institutional subscription to the source.  Nevertheless, many do offer free full-text, and if not, usually offer text or links that show the abstracts of the articles.  Links to books variously may open to full-text, or to the publishers' description of the book with or without downloadable selected chapters, reviews, and table of contents.  Books with links to Google Books often offer extensive previews of the books' text.
+''Many citations to articles listed below include links to full-text &mdash; in font-color <font color="blue"> blue</font>.  Accessing full-text may require personal or institutional subscription to the source.  Nevertheless, many sources do offer free full-text, and if not, usually offer text or links that show the abstracts of the articles.  Links to books variously may open to full-text, or to the publishers' description of the book with or without downloadable selected chapters, reviews, and table of contents.  Books with links to Google Books often offer extensive previews of the books' text.
 |}
 <br>
-<div class="references-small" style="-moz-column-count:2; column-count:2;">
+{{reflist|2}}[[Category:Suggestion Bot Tag]]
-<references />
-</div>

Hormesis: Difference between revisions

Latest revision as of 06:01, 29 August 2024

Contents

Introduction

Medicine or poison? Depends on dose

What doesn't kill you makes you stronger

Proposed mechanisms for hormesis

Controversial issues

History of hormesis concept

Definitional considerations

Mitochondrial hormesis (mitohormesis)

Hormesis and plant biology

Xenohormesis

Hormesis vs. homeopathy

References and notes cited in text as superscripts

Navigation menu

Hormesis: Difference between revisions

Latest revision as of 06:01, 29 August 2024

Introduction

Medicine or poison? Depends on dose

What doesn't kill you makes you stronger

Proposed mechanisms for hormesis

Controversial issues

History of hormesis concept

Definitional considerations

Mitochondrial hormesis (mitohormesis)

Hormesis and plant biology

Xenohormesis

Hormesis vs. homeopathy

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