Hormesis

In toxicology, hormesis refers to a quantitative and qualitative dose-response relationship—also called a concentration-effect relationship—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—i.e., with increasing concentration of the environmental agent the response is biphasic. 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.

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—a non-monotonic effect. 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. Excessive exercise, however, can lead to drug-like addictive behavioral responses.

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)

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)

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."

[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. "Examples include many chemicals, temperature, radiation, exercise, energy intake and others." 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" [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.

‘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.  

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, 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.

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.

Proposed mechanisms for hormesis

Holding ref:

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.

Thayer et al. write:

Cook and Calabrese (2006) make inaccurate claims about our perspective on hormesis (Thayer et al. 2005). 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). Previously, Calabrese and Baldwin (2003a) 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.

History of hormesis concept

Hormesiologist A.R.D. Stebbing offers a succinct account of the history of the phenomenon and concept of hormesis:

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.

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.

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.

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)

References cited by Professor Stebbing in the above excerpt:

Townsen and Luckey 1960 | Schultze 1888 | Hueppe 1896 | Southam and Ehrlich 1943 | Miller et al. 1945 | Davis and Hidu 1969 | Luckey 1956

Definitional considerations

Hormesiologists Edward J. Calabrese and Linda A. Baldwin provide an introduction to definitional considerations with the abstract of their paper, Defining Hormesis 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.

More recently, Vaiserman writes:

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

Mitochondrial hormesis (mitohormesis)

Holding refs:

Hormesis and plant biology

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

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. 

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.

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.

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.

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