Hormesis

Toxicologists use the term hormesis to refer to a quantitative and qualitative dose-response relationship, or concentration-effect relationship, between exposure of an organism to an environmental agent and the organism's response, characterized by the organism's biological response to the agent at certain low concentrations occurring in a direction opposite that expected from its effect observed at certain higher concentrations. For example, a toxin that inhibits a function of a biological component of the organism in certain known doses stimulates the function of that component at certain lower doses.

The fundamental characteristic of hormesis is its 'non-monotonic' or 'biphasic' feature, meaning the response to the agent in question changes direction with increasing or decreasing doses. The low dose-range where stimulation occurs &mdash; the stimulatory zone &mdash; may associate with beneficial or detrimental effect to the organism, though interest often concentrates on instances in which the low-dose effect confers benefit whereas the high-dose effect exhibits 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."

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. A bad thing, so to speak, arises from too much of a good thing. The example of the first aphorism applies also to the second aphorism. Thus the quantifiable, in-principle, biological phenomenon of ‘hormesis’ manifests itself.

In their 2008 New Scientist article entitled, "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". ''']

Biologists who specialize in the biochemical and physiological effects of toxic chemicals in living systems &mdash; 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. 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. "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.

Mattson and Calabrese add another twist to hormesis, defining 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 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. 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.

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':

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.

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. '

Controversial issues
Scientists have not universally accepted hormesis, though the discussion remains active. 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 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."

History of hormesis
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:

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.

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:

<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 10-400 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.